OtoRhinoLaryngology by Alexandros G.Sfakianakis

Τρίτη 2 Ιανουαρίου 2018

Homo- and heteroleptic Pt(II) complexes of ONN donor hydrazone and 4-picoline: A synthetic, structural and detailed mechanistic anticancer investigation.

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Homo- and heteroleptic Pt(II) complexes of ONN donor hydrazone and 4-picoline: A synthetic, structural and detailed mechanistic anticancer investigation.

Eur J Med Chem. 2018 Jan 01;143:1039-1052

Authors: Rahman FU, Bhatti MZ, Ali A, Duong HQ, Zhang Y, Yang B, Koppireddi S, Lin Y, Wang H, Li ZT, Zhang DW

Abstract
Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect. The overall anticancer effect of all these complexes was higher in liver (HepG2) and lung (H460) cancer cell lines and the effect of C2b and C3b was observed to be the highest among these 10 complexes. Therefore, we selected C2b and C3b to study their in vitro anticancer mechanism in HepG2 and H460 cancer cells. C2b and C3b changed cancer cell morphology and inhibited cell migration. The anticancer mechanistic studies demonstrated that C2b and C3b induced cell apoptosis, as evidenced by DAPI and AO/EB staining and flow cytometry analyses. Moreover, qRT-PCR and western blotting analysis showed that H460 and HepG2 cells treated with C2b and C3b significantly increased the expression of p53, p63, p21, p15, Bax and decreased Bcl-2 and c-Myc levels. The DNA binding property of these complexes was investigated by gel electrophoresis using pBR322 plasmid DNA. Taken together, the results obtained from the present study demonstrated the potentials of this new class of Pt(II) complexes in reduction of cell viability, suppression of cell migration and acceleration of apoptosis in different cancer cells.

PMID: 29232581 [PubMed - indexed for MEDLINE]

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The End of Nihilism: Systemic Therapy of Advanced Non-Small Cell Lung Cancer.

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The End of Nihilism: Systemic Therapy of Advanced Non-Small Cell Lung Cancer.

Annu Rev Med. 2017 Jan 14;68:153-168

Authors: Ernani V, Steuer CE, Jahanzeb M

Abstract
Lung cancer is the leading cause of cancer death in the United States and many other parts of the world. Non-small cell lung cancer (NSCLC) comprises 85-90% of lung cancers. Historically, the expected survival of patients with advanced disease has been estimated in months. In recent years, however, lung cancer has come to be seen as a treatable disease with multiple therapeutic options. Enormous advances in the understanding of its pathways and mechanisms have enabled personalized therapy in NSCLC. The evolving approach to therapy focuses on genomic profiling of the tumors to find molecular targets and develop specific agents for individualized therapy. In addition, maintenance therapy has emerged as a valid approach, and the choice of chemotherapy now varies by histology. Most recently, immunotherapy with checkpoint inhibitors has shown promising results, with impressive durations of response and a tolerable toxicity profile. Together, these discoveries have improved overall survival substantially in patient populations that have access to these advancements. We review the clinical data surrounding these impressive improvements.

PMID: 27618751 [PubMed - indexed for MEDLINE]

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Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors.

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors.

Oncotarget. 2017 Dec 05;8(63):106206-106221

Authors: Hontani K, Tsuchikawa T, Hiwasa T, Nakamura T, Ueno T, Kushibiki T, Takahashi M, Inoko K, Takano H, Takeuchi S, Dosaka-Akita H, Kuwatani M, Sakamoto N, Hatanaka Y, Mitsuhashi T, Shimada H, Shichinohe T, Hirano S

Abstract
Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.

PMID: 29290942 [PubMed]

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GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors.

GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors.

Lung Cancer. 2018 Jan;115:5-11

Authors: Jiang J, Wu X, Tong X, Wei W, Chen A, Wang X, Shao YW, Huang J

Abstract
OBJECTIVES: ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential.
MATERIALS AND METHODS: The GCC2-ALK fusion gene was identified by targeted next generation sequencing (NGS) from the tumor DNA samples, and its fusion product was confirmed by Sanger sequencing the cDNA product. The functional study of GCC2-ALK was performed in Ba/F3 cells with cell proliferation and viability assays. The activation of downstream signaling pathways of ALK and their responses to crizotinib inhibition were studied in HEK-293 and 293T cells with ectopic expression of GCC2-ALK. In parallel, disease progression in the patient was monitored by computed tomography scanning and targeted NGS of either liquid or tissue biopsy samples throughout and after crizotinib treatment.
RESULTS: Similarly to EML4-ALK, the GCC2-ALK fusion protein promotes IL-3-independent growth of Ba/F3 cells. Ectopic expression of GCC2-ALK leads to hyper-activation of ALK downstream signaling that can be inhibited by crizotinib. Crizotinib treatment of the patient resulted in 18 months of progression free survival without any trace of GCC2-ALK fusion in the liquid biopsies. Re-biopsy of a lung lesion at progression identified the re-occurrence of GCC2-ALK. The patient was then administrated with a second-generation ALK inhibitor, ceritinib, and received partial response until the last follow-up.
CONCLUSION: We identified and functionally validated GCC2-ALK as a constitutively activated fusion in NSCLC. The patient was benefited from crizotinib treatment initially and then ceritinib after progression, suggesting GCC2-ALK as a novel therapeutic target for ALK inhibitors.

PMID: 29290262 [PubMed - in process]

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Progression of Fibroadenoma to Malignant Phyllodes Tumour in a 14-Year Female.

Progression of Fibroadenoma to Malignant Phyllodes Tumour in a 14-Year Female.

J Coll Physicians Surg Pak. 2018 Jan;28(1):69-71

Authors: Faridi SH, Siddiqui B, Ahmad SS, Aslam M

Abstract
Phyllodes tumours are uncommon breast tumours which account for less than 1% of all breast neoplasms. High-grade malignant phyllodes tumour is a very rare but aggressive breast malignancy and forms approximately 15-30% of all phyllodes tumours. The transformation of a benign fibroadenoma into a malignant phyllodes tumour in a teenaged female is even rarer. We report here an interesting case of malignant phyllodes tumour in a 14-year female patient who was operated twice previously with the diagnosis of complex fibroadenoma in the same breast. There was a large tumour involving whole of the breast and infiltrating the skin. The patient was operated and total mastectomy was done. Diagnosis was confirmed after histopathological examination and immunohistochemistry of the resected specimen. Patient received adjuvant radiotherapy and there was no recurrence on 6-month follow-up. Owing to the rare occurrence of malignant phyllodes tumour in this age group along with previous operations for complex fibroadenoma, this case is being reported here.

PMID: 29290198 [PubMed - in process]

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The Expression of Matrix Metalloproteinases in Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-expressing Cancer of Apocrine Origin.

The Expression of Matrix Metalloproteinases in Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-expressing Cancer of Apocrine Origin.

Anticancer Res. 2018 Jan;38(1):113-120

Authors: Kambayashi Y, Fujimura T, Furudate S, Lyu C, Hidaka T, Kakizaki A, Sato Y, Tanita K, Aiba S

Abstract
Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD). Since EMPD is a skin adenocarcinoma of apocrine gland origin that expresses high levels of RANKL and matrix metalloproteinase (MMP) 7, and EMPD is associated with the presence of RANK+ M2 macrophages, we hypothesized that tumor-associated macrophages (TAMs) in adenocarcinomas such as PCAC might also express RANKL and MMP7.
MATERIALS AND METHODS: We employed immunohistochemical staining of RANKL and MMP7 in the lesional skin from five patients with PCAC, and microarray analysis of MMPs using human monocyte-derived macrophages.
RESULTS: According to DNA microarray analysis, the expression of MMP1 and MMP25 was augmented. The DNA microarray results were verified by using real-time polymerase chain reaction (RT-PCR). Immunohistochemical staining of MMP1 and MMP25 as well as chemokine (C-C motif) ligand (CCL) 5 in the lesional skin from five patients with PCAC showed a substantial number of MMP1-bearing cells and MMP25-bearing cells, as well as CCL5-producing cells, that were distributed in the lesional skin.
CONCLUSION: Our study suggests that the RANKL/RANK pathway contributes to the development and maintenance of the immunosuppressive tumor microenvironment and denosumab may be a promising adjuvant therapy targeting TAMs in cancer of apocrine origin.

PMID: 29277763 [PubMed - indexed for MEDLINE]

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A Rare Case of Urachal Carcinoma Metastatic to Thoracic Vertebra Detected by FDG PET/CT.

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A Rare Case of Urachal Carcinoma Metastatic to Thoracic Vertebra Detected by FDG PET/CT.

Clin Nucl Med. 2017 Jul;42(7):544-546

Authors: Yang G, Wang Z, Liu S, Wu F, Li D

Abstract
Both chest radiography and MRI scan showed compression fracture of the T6 vertebral body in a 33-year-old man who presented with back pain. Because of the absence of predisposing factors for compression fracture, a pathologic fracture was considered. For this reason, an FDG PET/CT was performed. The images revealed not only the abnormal activity in the known T6 vertebral body but also an additional activity immediately anterosuperior to the urinary bladder in a partially calcified soft tissue nodule. A mucinous adenocarcinoma of urachus with solitary bone metastasis was confirmed histopathologically.

PMID: 28481799 [PubMed - indexed for MEDLINE]

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Blastic Plasmacytoid Dendritic Cell Neoplasm Evaluated by FDG PET/CT.

Blastic Plasmacytoid Dendritic Cell Neoplasm Evaluated by FDG PET/CT.

Clin Nucl Med. 2017 Jul;42(7):551-552

Authors: Li ZG, Mu HY

Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy. A 34-year-old man with a biopsy-proven BPDCN underwent FDG PET/CT for staging. FDG PET/CT revealed multiple mild FDG-avid cutaneous lesions on the chest and back, involvement of left inguinal lymph node, and a markedly increased FDG-avid subcutaneous mass in the left lower leg.

PMID: 28394841 [PubMed - indexed for MEDLINE]

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Multicentric Reticulohistiocytosis Mimicking Malignancy on 18F-FDG PET/CT.

Multicentric Reticulohistiocytosis Mimicking Malignancy on 18F-FDG PET/CT.

Clin Nucl Med. 2017 Jul;42(7):567-568

Authors: Hotta M, Minamimoto R, Suzuki D, Takahashi A

Abstract
We report the case of a 75-year-old woman who underwent F-FDG PET/CT to evaluate the recurrence of urothelial carcinoma. PET/CT showed F-FDG-avid muscles and lymph nodes, mimicking recurrence. However, F-FDG uptake was also seen in multiple joints and subcutaneous tissue, representing an uncommon finding for recurrence. Further history taking revealed she had been pathologically diagnosed with multicentric reticulohistiocytosis (MRH) from skin biopsy, and the F-FDG PET/CT findings were consistent with MRH, a rare systemic inflammatory granulomatous disease of unknown etiology. Knowledge of the characteristic F-FDG PET/CT features of MRH is important to differentiate MRH from malignancy.

PMID: 28368895 [PubMed - indexed for MEDLINE]

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Early Detection of Bilateral Testicular Metastases From Prostatic Adenocarcinoma Using 68Ga-PSMA Ligand PET/CT.

Early Detection of Bilateral Testicular Metastases From Prostatic Adenocarcinoma Using 68Ga-PSMA Ligand PET/CT.

Clin Nucl Med. 2017 Jul;42(7):563-564

Authors: Weiberg D, Radner H, Derlin T, Thon WF

Abstract
We present the case of a 76-year-old man with biochemical relapse after primary therapy for prostate cancer. Ga prostate-specific membrane antigen (PSMA) ligand PET/CT performed for localization of recurrent disease revealed bilateral metastases to the testes. Histopathologic evaluation after bilateral orchiectomy revealed testicular metastases. Metastases to the testes are rare and usually seen in advanced stages. Ga-PSMA ligand PET/CT is a highly sensitive and specific imaging method for the detection of primary and metastatic prostate cancer and has refined diagnostic approaches. This case highlights the potential of PSMA-targeted PET/CT for detection of prostate cancer metastases, even in very unusual localizations.

PMID: 28368893 [PubMed - indexed for MEDLINE]

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Image of the Month: Multifocal 68Ga Prostate-Specific Membrane Antigen Ligand Uptake in the Skeleton in a Man With Both Prostate Cancer and Multiple Myeloma.

Image of the Month: Multifocal 68Ga Prostate-Specific Membrane Antigen Ligand Uptake in the Skeleton in a Man With Both Prostate Cancer and Multiple Myeloma.

Clin Nucl Med. 2017 Jul;42(7):547-548

Authors: Rauscher I, Maurer T, Steiger K, Schwaiger M, Eiber M

Abstract
Ga prostate-specific membrane antigen (PSMA) HBED-CC PET/CT in a 65-year-old man with first diagnosis of prostate cancer (PC) and a history of multiple myeloma showing multifocal PSMA ligand uptake in the skeleton with corresponding osteolytic lesions in CT. Although osteolytic bone metastases are very rare in PC, PSMA expression in PET raised the suspicion of PC bone metastases. Bone marrow biopsy excluded PC metastases with immunohistochemistry showing endothelial expression of PSMA in small vessels within the myeloma.

PMID: 28368889 [PubMed - indexed for MEDLINE]

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Lymphangioleiomyomatosis: A Monogenic Model of Malignancy.

Lymphangioleiomyomatosis: A Monogenic Model of Malignancy.

Annu Rev Med. 2017 Jan 14;68:69-83

Authors: Krymskaya VP, McCormack FX

Abstract
Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell-metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.

PMID: 28099079 [PubMed - indexed for MEDLINE]

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Postoperative surveillance of pediatric cerebellar pilocytic astrocytoma.

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Postoperative surveillance of pediatric cerebellar pilocytic astrocytoma.

J Neurooncol. 2016 Oct;130(1):149-154

Authors: Alford R, Gargan L, Bowers DC, Klesse LJ, Weprin B, Koral K

Abstract
The purpose of this study was to identify the optimal frequency and duration of magnetic resonance imaging follow-up in children who had gross totally resected cerebellar pilocytic astrocytomas (CPAs). Our hypothesis was that following two MR examinations, separated by at least 3 months, showing no evidence of tumor, gross totally resected CPAs did not recur and no further imaging follow-up was necessary. Retrospective review of Neuro-Oncology database from 1/2000 to 7/2013 yielded 53 patients with CPAs that had preoperative imaging and >2 years post-operative imaging follow-up available. Pilocytic astrocytomas with brainstem involvement and patients with neurofibromatosis type I were excluded. Preoperative tumor volumes were calculated. The dates and reports of the examinations were tabulated. The median number of follow-up examinations was 9 over a median follow-up time of 6.05 years (2.07-12.28 years). Two consecutive MR examinations over at least a 3 month span demonstrated the smallest negative likelihood ratio of future recurrence (0.15). There was no association of recurrence with preoperative tumor volume. Among the 35 patients with gross total resection of their tumor and greater than two negative follow-up examinations, one recurrence (2.9 %) was identified, occurring 6.4 years after initial resection. Gross totally resected pediatric CPAs can recur, but this is exceedingly rare. Frequent surveillance (every 3-6 months) is suggested in patients with CPAs until absence of tumor is concluded on imaging and documented on two consecutive studies spaced at least 3 months apart. The likelihood of recurrence thereafter is low.

PMID: 27502785 [PubMed - indexed for MEDLINE]

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Otorhinolaryngological manifestations in head trauma: A prospective study of the epidemiology, clinical presentations, management, and outcomes.

Otorhinolaryngological manifestations in head trauma: A prospective study of the epidemiology, clinical presentations, management, and outcomes.

Int J Crit Illn Inj Sci. 2017 Oct-Dec;7(4):231-235

Authors: Adoga AA, Ozoilo KN, Iduh AA, Mugu JG

Abstract
Background: Otorhinolaryngological injuries following head trauma may be missed, overlooked, or forgotten in the acute phase resulting in worsened management outcomes. This study aims to report the epidemiology, clinical presentations, management, and outcomes of otorhinolaryngological injuries in head trauma with a view to creating awareness for early recognition and prompt treatment.
Patients and Methods: Head injured patients consecutively presenting over a 5-year period were prospectively studied for age, gender, otorhinolaryngological presentations, interventions, and outcome of interventions. Data obtained were statistically analyzed.
Results: There were 91 (1.3%) otorhinolaryngological presentations among 7109 head injured patients. Mean age of 34 years, standard deviation = ±15.6 with a male:female ratio of 2.4:1. Severe head injury (Glasgow coma scale <9) occurred in 46 (50.5%) patients. Patients aged 30-39 years were mostly affected (n = 30; 32.9%). Most injuries were from motor vehicular accidents (n = 61; 67%) and assaults (n = 23; 25.3%). The most common otorhinolaryngological presentations were cerebrospinal fluid (CSF) rhinorrhea (n = 26; 28.6%) and CSF otorrhea (n = 25; 27.5%). Conservative management was achieved in 59.3% of patients. Mean time of hospital presentation was 13.8 h. There was no statistical correlation between outcomes and each of etiology and time of presentation (P values 0.18 and 0.9, respectively). Seventy-five (82.4%) were discharged without neurological deficits. A case fatality rate of 6.6% was recorded.
Conclusion: Frontal skull base and temporal bone fractures with CSF rhinorrhea and otorrhea are the most common injuries occurring mostly in young active males with favorable outcomes following conservative management.

PMID: 29291176 [PubMed]

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Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser-induced CNV mouse model of neovascular AMD.

Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser-induced CNV mouse model of neovascular AMD.

Exp Eye Res. 2017 Dec 25;:

Authors: Wei X, Zhang T, Yao Y, Zeng S, Li M, Xiang H, Zhao C, Cao G, Li M, Wan R, Yang P, Yang J

Abstract
Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 ± 0.2939 vs 5.202 ± 0.9001 (P = .0133) at day 7th post laser-induced CNV, 1.138 ± 0.4334 vs 3.122 ± 0.3466 (P = .0064) at day 14th, 1.401 ± 0.6577 vs 2.781 ± 0.9815 (P = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T1/2 in retina was 3.81 ± 0.77 h, the Tmax was 4.60 ± 0.73 h, the AUC0-∞ was 110448.51 ± 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD.

PMID: 29284110 [PubMed - as supplied by publisher]

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Δευτέρα 1 Ιανουαρίου 2018

How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.

How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.

Rhinology. 2017 Dec 31;:

Authors: Lin KY, Chen PY, Yeh TH

Abstract
Various factors have been proposed to be related to refractory chronic rhinosinusitis (CRS). Treatment for refractory CRS is challenging for ear, nose, and throat (ENT) surgeons. The aim of the study was to determine the clinical features associated with the severity of CRS that may necessitate revision surgery by eliminating the bias of the surgeons technique using standardizing surgical procedures. Sinus wall thickness and blood eosinophilia, which may represent the depth of inflammation in CRS, are associated with the need for revision surgery. We found that, when the thickness of the postero-lateral maxillary sinus wall is more than 3.03 mm, there is an increased probability for a need for revision surgery. CRS patients with thickened sinus walls were found to have poorer outcomes. Further research is needed in order to justify this type of surgical procedure for CRS.

PMID: 29289975 [PubMed - as supplied by publisher]

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A Vascular Endothelial Growth Factor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human Blood Vessel Model for the Study of Anti-Angiogenic Drugs.

A Vascular Endothelial Growth Factor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human Blood Vessel Model for the Study of Anti-Angiogenic Drugs.

EBioMedicine. 2017 Dec 20;:

Authors: Pauty J, Usuba R, Cheng IG, Hespel L, Takahashi H, Kato K, Kobayashi M, Nakajima H, Lee E, Yger F, Soncin F, Matsunaga YT

Abstract
Angiogenesis is the formation of new capillaries from pre-existing blood vessels and participates in proper vasculature development. In pathological conditions such as cancer, abnormal angiogenesis takes place. Angiogenesis is primarily carried out by endothelial cells, the innermost layer of blood vessels. The vascular endothelial growth factor-A (VEGF-A) and its receptor-2 (VEGFR-2) trigger most of the mechanisms activating and regulating angiogenesis, and have been the targets for the development of drugs. However, most experimental assays assessing angiogenesis rely on animal models. We report an in vitro model using a microvessel-on-a-chip. It mimics an effective endothelial sprouting angiogenesis event triggered from an initial microvessel using a single angiogenic factor, VEGF-A. The angiogenic sprouting in this model is depends on the Notch signaling, as observed in vivo. This model enables the study of anti-angiogenic drugs which target a specific factor/receptor pathway, as demonstrated by the use of the clinically approved sorafenib and sunitinib for targeting the VEGF-A/VEGFR-2 pathway. Furthermore, this model allows testing simultaneously angiogenesis and permeability. It demonstrates that sorafenib impairs the endothelial barrier function, while sunitinib does not. Such in vitro human model provides a significant complimentary approach to animal models for the development of effective therapies.

PMID: 29289530 [PubMed - as supplied by publisher]

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Rerouting the internal thoracic pedicle: a novel solution for maxillofacial reconstruction in vessel-depleted situations? A preliminary anatomic study.

Rerouting the internal thoracic pedicle: a novel solution for maxillofacial reconstruction in vessel-depleted situations? A preliminary anatomic study.

Surg Radiol Anat. 2017 Dec 30;:

Authors: Morel F, Crampon F, Adnot J, Litzler PY, Duparc F, Trost O

Abstract
PURPOSE: Microsurgical reconstruction in a vessel-depleted neck is a challenge due to the lack of reliable vessels in or nearby the host site. The use of the internal thoracic pedicle (ITP) by rib section or sparring is a limited option due to the small length of the pedicle of some flaps. However, in cardiac surgery, the internal thoracic artery (ITA) is widely used for myocardial revascularization, providing a long and versatile pedicle. We aimed at determining precise anatomical bases for the use of the ITP, approached by sternotomy and rerouted in the neck, as recipient vessels for free-flap facial reconstructions.
METHODS: We performed a descriptive single centre anatomical study on 20 formalin-embalmed cadavers. The ITP was harvested on both sides from the emergence of the artery under the brachiocephalic vein to its terminal division. The level reached by the ITP in the cervicofacial area was described. Distal arterial and venous diameters, pedicle length and other parameters were measured.
RESULTS: In at least 85% of the cases, the ITP reached the mandibular angle. The mean diameter at the distal extremity for the ITA was 2.36 ± 0.15, and 2.48 ± 0.19 mm for the committing vein. The mean length of the ITP was 177.3 mm.
CONCLUSION: Rerouting the ITP towards the cervicofacial area could provide a reliable pedicle for free-flap reconstructions in patients with a vessel-depleted neck but it should be limited to selected patients. This novel solution for situations where current techniques are unfeasible warrants further clinical research.

PMID: 29289988 [PubMed - as supplied by publisher]

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A prospective, randomized-controlled pilot study comparing closed suction versus negative pressure drains for panniculectomy patients.

A prospective, randomized-controlled pilot study comparing closed suction versus negative pressure drains for panniculectomy patients.

J Plast Reconstr Aesthet Surg. 2017 Nov 28;:

Authors: Walker ME, Tsay C, Broer PN, Zhu VZ, Sturrock T, Ng R, Scoutt LM, Thomson JG, Kwei SL

PMID: 29289501 [PubMed - as supplied by publisher]

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Perforator mapping reduces the operative time of DIEP flap breast reconstruction: A systematic review and meta-analysis of preoperative ultrasound, computed tomography and magnetic resonance angiography.

Perforator mapping reduces the operative time of DIEP flap breast reconstruction: A systematic review and meta-analysis of preoperative ultrasound, computed tomography and magnetic resonance angiography.

J Plast Reconstr Aesthet Surg. 2017 Dec 12;:

Authors: Wade RG, Watford J, Wormald JCR, Bramhall RJ, Figus A

Abstract
BACKGROUND: Prior to DIEP flap breast reconstruction, mapping the perforators of the lower abdominal wall using ultrasound, computed tomography angiography (CTA) or magnetic resonance angiography (MRA) reduces the risk of flap failure. This review aimed to investigate the additional potential benefit of a reduction in operating time.
METHODS: We systematically searched the literature for studies concerning adult women undergoing DIEP flap breast reconstruction, which directly compared the operating times and adverse outcomes for those with and without preoperative perforator mapping by ultrasound, CTA or MRA. Outcomes were extracted, data meta-analysed and the quality of the evidence appraised.
RESULTS: Fourteen articles were included. Preoperative perforator mapping by CTA or MRA significantly reduced operating time (mean reduction of 54 minutes [95% CI 3, 105], p = 0.04), when directly compared to DIEP flap breast reconstruction with no perforator mapping. Further, perforator mapping by CTA was superior to ultrasound, as CTA saved more time in theatre (mean reduction of 58 minutes [95% CI 25, 91], p < 0.001) and was associated with a lower risk of partial flap failure (RR 0.15 [95% CI 0.04, 0.6], p = 0.007). All studies were at risk of methodological bias and the quality of the evidence was very low.
CONCLUSIONS: The quality of research regarding perforator mapping prior to DIEP flap breast reconstruction is poor and although preoperative angiography appears save operative time, reduce morbidity and confer cost savings, higher quality research is needed.
REGISTRATION: PROSPERO ID CRD42017065012.

PMID: 29289500 [PubMed - as supplied by publisher]

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Founder mutation in IKBKAP gene causes vestibular impairment in familial dysautonomia.

Founder mutation in IKBKAP gene causes vestibular impairment in familial dysautonomia.

Clin Neurophysiol. 2017 Nov 26;129(2):390-396

Authors: Gutiérrez JV, Kaufmann H, Palma JA, Mendoza-Santiesteban C, Macefield VG, Norcliffe-Kaufmann L

Abstract
OBJECTIVE: To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia.
METHODS: Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead.
RESULTS: cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous.
CONCLUSIONS: The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs.
SIGNIFICANCE: Vestibular abnormalities may contribute to the gait ataxia in FD.

PMID: 29289840 [PubMed - as supplied by publisher]

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Implementation of Trauma Center and Massive Transfusion Protocol Improves Outcomes for Major Trauma Patients: A Study at a Single Institution in Korea.

Implementation of Trauma Center and Massive Transfusion Protocol Improves Outcomes for Major Trauma Patients: A Study at a Single Institution in Korea.

World J Surg. 2017 Dec 31;:

Authors: Hwang K, Kwon J, Cho J, Heo Y, Lee JC, Jung K

Abstract
BACKGROUND: This study evaluated the effectiveness and clinical outcomes of the implementation of a trauma center and massive transfusion protocol (TCMTP) in a developing country without a well-established trauma system.
METHODS: We included patients (1) aged >15 years, (2) with an Injury Severity Score >15, (3) who received ≥10 units of packed red blood cells (PRBCs) within 24 h, (4) who directly visited our institution from 2010 to 2016, and (5) who survived for ≥24 h. Patients treated during the post-TCMTP period (2015-2016) were compared with historical groups treated pre-TCMTP (2010-2012) and interim-TCMTP (2013-2014). Demographics, transfusion and fluid therapy performance, and clinical outcomes were compared between the three groups.
RESULTS: Overall, 190 patients were included: 64, 64, and 62 patients in the pre-TCMTP, interim-TCMTP, and post-TCMTP groups, respectively. Comparison between the three groups revealed significant differences in the fresh-frozen plasma/PRBC ratio (p = 0.001) and crystalloid infusion (p = 0.007); these variables gradually increased from pre- to post-TCMTP. Conversely, colloid infusion showed a reduction post-TCMTP (p < 0.001). Kaplan-Meier curves revealed that the 90-day survival rate was significantly higher in the post-TCMTP group (pre-TCMTP: 45.3 vs. 75.8%, p = 0.001; interim-TCMTP: 56.3 vs. 75.8%, p = 0.027). In Cox regression hierarchical survival analysis, TCMTP showed a hazard ratio for mortality of 0.380 after adjusting for all potentially confounding factors.
CONCLUSIONS: Our results suggest that building trauma centers and establishing a massive transfusion protocol according to the specific situations of a country will help improve outcomes for major trauma patients, even in developing countries without a well-established trauma system.

PMID: 29290073 [PubMed - as supplied by publisher]

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Operations for Suspected Neoplasms in a Resource-Limited Setting: Experience and Challenges in the Eastern Democratic of Congo.

Operations for Suspected Neoplasms in a Resource-Limited Setting: Experience and Challenges in the Eastern Democratic of Congo.

World J Surg. 2017 Dec 31;:

Authors: Kalisya LM, Bake JF, Bigabwa R, Rothstein DH, Cairo SB

Abstract
INTRODUCTION: Surgery is an essential component of a functional health system, with surgical conditions accounting for nearly 11-15% of world disability. While communicable diseases continue to burden low- and low-middle-income countries, non-communicable diseases, such as cancer, are an important cause of morbidity and mortality worldwide. Preliminary data on malignancies in low- and middle-income countries, specifically in Africa, suggest a higher mortality compared to other regions of the world, a difference partially explained by limited availability of screening and early detection systems as well as poorer access to treatment.
OBJECTIVE: To evaluate the diagnosed tumor burden in the Eastern Democratic Republic of Congo (DRC) and review literature on existing and suspected barriers to accessing appropriate oncologic care.
METHODS: This is a retrospective study carried out at Healthcare, Education, community Action, and Leadership development Africa, a 197-bed tertiary referral hospital, in the Province of North Kivu, along the eastern border of the DRC from 2012 to 2015. Patient charts were reviewed for diagnoses of presumed malignancy with biopsy results.
RESULTS: A total of 252 cases of suspected cancer were reviewed during the study period; 39.7% were men. The average age of patients was 43 years. Amongst adult patients, the most common presenting condition involved breast lesions with 5.8% diagnosis of fibrocystic breast changes and 2.9% invasive ductal carcinoma of the breast. 37.3% of female patients had lesions involving the cervix or uterus. The most common diagnosis amongst male adults was prostate disease (16.7% of men). For pediatric patients, the most common diagnoses involved bone and/or cartilage (27.3%) followed by skin and soft tissue lesions (20.0%). All patients underwent surgical resection of lesions; some patients were advised to travel out of country for chemotherapy and radiation for which follow-up data are unavailable.
CONCLUSION: Adequate and timely treatment of malignancy in the DRC faces a multitude of challenges. Access to surgical services for diagnosis and management as well as chemotherapeutic agents is prohibitively limited. Increased collaboration with local clinicians and remote specialist consultants is needed to deliver subspecialty care in resource-poor settings.

PMID: 29290072 [PubMed - as supplied by publisher]

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Hakim Mohammad: A Persian Military Surgeon in Safavid Era (1501-1736 CE).

Hakim Mohammad: A Persian Military Surgeon in Safavid Era (1501-1736 CE).

World J Surg. 2017 Dec 31;:

Authors: Khodaie SA, Ghaffari F, Zargaran A, Naseri M

Abstract
BACKGROUND: Wars and injuries have accompanied mankind throughout history. Physicians and surgeons from various civilizations made difficult attempts to manage wounds and injuries. Among various civilizations, the Persian Empires had great armies which were well equipped. One of the most important organizations in Persian troops was the military surgery.
METHODS: This study presents a brief biography of Hakim Mohammad (a military surgeon in Safavid era) and introduces his book, Dhakhira-yi-Kamilah.
RESULTS AND DISCUSSION: Safavid kings (1501-1736 CE) with unifying all of Persian regions and provinces reconstructed the Persian Empire. Great scholars and physicians were raised in this era. It seems that Persian physicians and surgeons were well trained in Safavid era and many of them were even employed by other countries like Ottoman Empire and India. Hakim Mohammad as a military surgeon was one of such physicians who served in Ottoman Empire for some time. He gathered his surgical experiences and others in the book of Dhakhira-yi-Kamilah. This book was written in Persian. He has mainly written about the management of wounds and practical techniques. Later, he came back to his homeland and dedicated his book to the king of Persia.

PMID: 29290071 [PubMed - as supplied by publisher]

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One-Hour Postoperative Parathyroid Hormone Levels Do Not Reliably Predict Hypocalcemia After Thyroidectomy.

One-Hour Postoperative Parathyroid Hormone Levels Do Not Reliably Predict Hypocalcemia After Thyroidectomy.

World J Surg. 2017 Dec 31;:

Authors: Sahli Z, Najafian A, Kahan S, Schneider EB, Zeiger MA, Mathur A

Abstract
INTRODUCTION: Hypocalcemia is a well-known complication after total thyroidectomy. Studies have indicated that the presence of low postoperative parathyroid hormone (PTH) levels can predict hypocalcemia. However, definitive study designs are lacking. The aim of this study was to determine whether postoperative PTH alone can accurately predict postoperative biochemical hypocalcemia.
METHODS: Under IRB approval, a prospective study of 218 consecutive patients who underwent total or completion thyroidectomy by two surgeons between June 2014 and June 2016 was performed. Biochemical hypocalcemia was defined as ionized calcium <1.13 mmol/L or serum calcium <8.4 mg/dL at any time postoperatively. Three PTH thresholds, <10, <20 pg/mL, and >50% drop in PTH 1 h postoperatively from baseline were examined.
RESULTS: Postoperative PTH < 10 pg/mL had a sensitivity of 36.5% (95% CI 27.4-46.3%) and a specificity of 89.2% (95% CI 81.9-94.3%). Postoperative PTH < 20 pg/mL had a sensitivity of 66.4% (95% CI 56.6-75.2%) and a specificity of 67.6% (95% CI 58.0-76.2%). Postoperative PTH decrease >50% had a sensitivity of 63.4% (95% CI 53.2-72.7%) and a specificity of 72.5% (95% CI 62.5-81.0%). Across all PTH thresholds, the false-negative rate was 33.6-63.5% indicating that up to 64% of patients with a normal PTH level could have been discharged without appropriate calcium supplementation. The false-positive rate was 10.8-32.4% indicating that up to 32.4% of patients with low PTH could have been treated with calcium supplementation unnecessarily.
CONCLUSION: Following total thyroidectomy, PTH levels are unreliable in predicting hypocalcemia. Additional prospective studies are needed to understand the true utility of PTH levels post-thyroidectomy.

PMID: 29290070 [PubMed - as supplied by publisher]

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Preoperative Prognostic Nutritional Index Predicts Long-Term Surgical Outcomes in Patients with Esophageal Squamous Cell Carcinoma.

Preoperative Prognostic Nutritional Index Predicts Long-Term Surgical Outcomes in Patients with Esophageal Squamous Cell Carcinoma.

World J Surg. 2017 Dec 31;:

Authors: Hirahara N, Tajima Y, Fujii Y, Kaji S, Yamamoto T, Hyakudomi R, Taniura T, Miyazaki Y, Kishi T, Kawabata Y

Abstract
BACKGROUND: The purpose of the present study is to investigate the utility of prognostic nutritional index (PNI) as a simple and readily available marker in esophageal squamous cell carcinoma (ESCC).
METHODS: We retrospectively analyzed 169 patients who underwent potentially curative esophagectomy, for histologically verified ESCC. We decided to set the optimal cutoff value for preoperative PNI levels at 49.2, based on the cancer-specific survival (CSS) and the overall survival (OS) by receiver operating characteristic curve analysis.
RESULTS: Multivariate logistic regression analysis identified that TNM pStage III [hazard ratio (HR) 3.261, p < 0.0001] and PNI < 49.2 (HR 3.887, p < 0.0001) were confirmed as independent poor predictive factors for CSS, and age >70 (HR 2.024, p < 0.0042), TNM pStage III (HR 2.510, p = 0.0002), and PNI < 49.2 (HR 2.248, p = 0.0013) were confirmed as independent poor predictive factors for OS. In non-elderly patients, TNM pStage III (CSS; HR 3.488, p < 0.0001, OS; HR 2.615, p = 0.0007) and PNI < 49.2 (CSS; HR 3.849, p < 0.0001, OS; HR 2.275, p = 0.001) were confirmed as independent poor predictive factors for CSS, and OS when multivariate logistic regression analysis was applied. But in elderly patients, univariate analyses demonstrated that the TNM pStage III was the only significant risk factor for CSS (HR 3.701, p = 0.0057) and OS (HR 1.974, p = 0.0224).
CONCLUSIONS: The PNI was a significant and independent predictor of CSS and OS of ESCC patients after curative esophagectomy. The PNI was cost-effective and readily available, and it could act as a marker of survival.

PMID: 29290069 [PubMed - as supplied by publisher]

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Topical Minoxidil Versus Topical Diltiazem for Chemical Sphincterotomy of Chronic Anal Fissure: A Prospective, Randomized, Double-Blind, Clinical Trial.

Topical Minoxidil Versus Topical Diltiazem for Chemical Sphincterotomy of Chronic Anal Fissure: A Prospective, Randomized, Double-Blind, Clinical Trial.

World J Surg. 2017 Dec 31;:

Authors: Alvandipour M, Ala S, Khalvati M, Yazdanicharati J, Koulaeinejad N

Abstract
BACKGROUND: Anal fissure is a common anorectal problem causing severe pain and discomfort to the patients. Chemical sphincterotomy has emerged as a noninvasive alternative to the surgical methods of fissure treatment. The objective of this study was evaluation of the efficacy and the adverse effects of topically applied minoxidil in chemical sphincterotomy of chronic anal fissure in comparison with topical diltiazem.
METHODS: A total of 88 patients with chronic anal fissure aged between 15 and 65 years were included in this double-blind, randomized clinical trial and were randomly assigned to either 0.5% minoxidil cream or 2% diltiazem cream twice daily for 2 weeks. The pain intensity, bleeding, wound healing, itching, headache, dizziness, significant drop in blood pressure, allergy and fissure relapse were assessed on a monthly basis for 2 months.
RESULTS: Both diltiazem and minoxidil reduced the pain, bleeding and improved fissure healing with no significant difference. There were no between-groups differences in the frequencies of adverse effects, except for itching which was slightly higher with minoxidil during the first month. Allergy occurred in two patients in the minoxidil group, which was not severe and did not lead to discontinuation of the trial.
CONCLUSION: Topically administered minoxidil is of equal efficacy as diltiazem in the treatment of chronic anal fissure with low frequency of adverse effects. Thus, it can be considered as an agent for chemical sphincterotomy of anal fissure, but the itching at the beginning of the treatment can affect the adherence of the patient to treatment. Trial registration number IRCT2015041414483N6 (the full trial protocol could be accessed online at www.irct.ir ).

PMID: 29290068 [PubMed - as supplied by publisher]

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Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells.

Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells.

Cancer Chemother Pharmacol. 2017 Dec 30;:

Authors: Fedorchuk O, Susak Y, Rudyk M, Senchylo N, Khranovska N, Skachkova O, Skivka L

Abstract
PURPOSE: Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
METHODS: Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
RESULTS: When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
CONCLUSION: Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

PMID: 29290023 [PubMed - as supplied by publisher]

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Avoiding the ingestion of cytotoxic concentrations of ethanol may reduce the risk of cancer associated with alcohol consumption.

Avoiding the ingestion of cytotoxic concentrations of ethanol may reduce the risk of cancer associated with alcohol consumption.

Drug Alcohol Depend. 2017 Dec 27;183:201-204

Authors: Guillén-Mancina E, Calderón-Montaño JM, López-Lázaro M

Abstract
Alcohol consumption is a known risk factor for cancer. Almost 6% of all cancers worldwide are attributable to alcohol use. Approximately half of them occur in tissues highly exposed to ethanol, such as the oral cavity, pharynx, upper larynx and esophagus. However, since ethanol is not mutagenic and the mutagenic metabolite of ethanol (acetaldehyde) is mainly produced in the liver, it is unclear why alcohol consumption preferentially exerts a local carcinogenic effect. Recent findings indicate that the risk of cancer in a tissue is strongly correlated with the number of stem cell divisions accumulated by the tissue; the accumulation of stem cell divisions leads to the accumulation of cancer-promoting errors such as mutations occurring during DNA replication. Since cell death activates the division of stem cells, we recently proposed that the possible cytotoxicity of ethanol on the cells lining the tissues in direct contact with alcoholic beverages could explain the local carcinogenic effect of alcohol. Here we report that short-term exposures (2-3 s) to ethanol concentrations between 10% and 15% start to cause a marked cytotoxic effect on human epithelial keratinocytes in a concentration-dependent manner. We propose that choosing alcoholic beverages containing non-cytotoxic concentrations of ethanol, or diluting ethanol to non-cytotoxic concentrations, may be a simple and effective way to reduce the risk of cancers of the oral cavity, pharynx, larynx and esophagus in alcohol users. This preventive strategy may also reduce the known synergistic effect of alcohol drinking and tobacco smoking on the risk of these cancers.

PMID: 29289868 [PubMed - as supplied by publisher]

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The Effectiveness of the EASE Scale in the Development of a Vocal Warm-up Program for an Amateur Choir.

The Effectiveness of the EASE Scale in the Development of a Vocal Warm-up Program for an Amateur Choir.

J Voice. 2017 Dec 28;:

Authors: Marchand DLP, Kavaliunas FS, Cassol M

Abstract
OBJECTIVES: This study aims to assess the effectiveness of the EASE-BR (Evaluation of the Ability to Sing Easily for Brazil) protocol in the development of a vocal warm-up program for members of an amateur choir.
STUDY DESIGN: This is a prospective cross-sectional study measuring pre- and postintervention results at two moments.
METHODS: Forty-four subjects filled out a questionnaire to characterize the sample and underwent two major applications of the EASE-BR scale-the first to determine the group's vocal requirements and the second to assess the performance after the application of a customized vocal warm-up routine.
RESULTS: Overall reduction of the scores in the postintervention moment has been determined. The score of 16 of the questions (72.7%) showed a statistically relevant reduction after the intervention.
CONCLUSIONS: The EASE-BR scale proved a valuable assessment tool and its use may help develop customized vocal warm-up programs for different types of singers.

PMID: 29289412 [PubMed - as supplied by publisher]

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Sialendoscopy in treatment of adult chronic recurrent parotitis without sialolithiasis.

Sialendoscopy in treatment of adult chronic recurrent parotitis without sialolithiasis.

Eur Arch Otorhinolaryngol. 2017 Dec 30;:

Authors: Jokela J, Haapaniemi A, Mäkitie A, Saarinen R

Abstract
OBJECTIVE: The aim of this prospective study was to evaluate the efficacy of sialendoscopy in the management of adult chronic recurrent parotitis without sialolithiasis. In addition, preliminary results of an initial randomized placebo-controlled trial of single-dose intraductal steroid injection given concurrently with sialendoscopy, are presented.
METHODS: Forty-nine adult patients with chronic recurrent parotitis without sialoliths were included in this study. They underwent sialendoscopy and were randomized to receive either a concurrent intraductal injection of isotonic saline solution or 125 mg of hydrocortisone. Symptom severity was evaluated with visual analogue scale (VAS) and by recording symptom frequency and course with a multiple-choice questionnaire completed preoperatively and at 3, 6, and 12 months after the procedure.
RESULTS: The mean VAS score was 5.6 preoperatively and dropped to 2.9 at 3 months, 3.0 at 6 months, and 2.7 at 12 months after the procedure. The VAS score and the frequency of symptoms were significantly lower at 3 (p < 0.001), 6 (p < 0.001) and 12 (p < 0.001) months after the procedure when compared with the preoperative scores indicating that sialendoscopy reduces the symptoms of recurrent parotitis. However, complete permanent resolution of symptoms was rare. Single-dose steroid injection concomitant to sialendoscopy provided no additional benefit, but the current study is not sufficiently powered to determine a clinical difference between the steroid and non-steroid groups.
CONLUSION: Sialendoscopy appears to reduce the symptoms of chronic recurrent parotitis. While total permanent symptom remission is rare, sialendoscopy can be considered a safe and relatively efficacious treatment method for this patient group.

PMID: 29290052 [PubMed - as supplied by publisher]

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Rotavirus Infection as a Frequent Cause of Neonatal Fever.

Rotavirus Infection as a Frequent Cause of Neonatal Fever.

Pediatr Int. 2017 Dec 31;:

Authors: Kang HN, Park HK, Lee HJ, Moon JH, Oh JW, Kim CR

Abstract
BACKGROUND: Fever rather than diarrhea or vomiting was the most common symptom of neonatal rotavirus(RV) infection in our previous study. We investigated if RV infection is a major cause of neonatal fever and we compared the clinical characteristics of bacterial infections, viral infections and unknown causes of neonatal fever.
METHOD: We reviewed the electronic medical records of 48 newborns of ≤ 28 days who were admitted to the Special Care Nursery of Hanyang University Guri Hospital for fever (≥ 38°C) from 2005 to 2009. All the newborns underwent CBC, urinalysis, C-reactive protein, cultures of blood, urine, and CSF as well as stool RV ELISA. Respiratory virus PCR for cough or rhinorrhea, and stool culture for diarrhea were also done.
RESULTS: All the babies were term, mean age 13±8 days and peak body temperature 38.5±0.5°C. The causes of neonatal fever were viral (44%), bacterial (10%) and unknown (46%). The viral infections included RV (n=12), enterovirus (n=6), respiratory syncytial virus (n=2), and rhinovirus (n=1). All the rotavirus genotypes were G4P[6]. Only 3 of 12 RV-infected febrile newborns had diarrhea. The bacterial infections included 3 urinary tract infections (2 Escherichia coli and 1 Klebsiella pneumoniae), and 2 sepsis and meningitis (all Streptococcus agalactiae).
CONCLUSIONS: RV infection is the most common single cause of neonatal fever. It may be necessary to include stool RV tests for febrile newborns.

PMID: 29290098 [PubMed - as supplied by publisher]

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Contemporary Patterns of Multidisciplinary Care in Patients With Muscle-invasive Bladder Cancer.

Contemporary Patterns of Multidisciplinary Care in Patients With Muscle-invasive Bladder Cancer.

Clin Genitourin Cancer. 2017 Dec 06;:

Authors: Harshman LC, Tripathi A, Kaag M, Efstathiou JA, Apolo AB, Hoffman-Censits JH, Stadler WM, Yu EY, Bochner BH, Skinner EC, Downs T, Kiltie AE, Bajorin DF, Guru K, Shipley WU, Steinberg GD, Hahn NM, Sridhar SS

Abstract
BACKGROUND: Multidisciplinary clinics integrate the expertise of several specialties to provide effective treatment to patients. This exposure is especially relevant in the management of muscle-invasive bladder cancer (MIBC), which requires critical input from urology, radiation oncology, and medical oncology, among other supportive specialties.
MATERIALS AND METHODS: In the present study, we sought to catalog the different styles of multidisciplinary care models used in the management of MIBC and to identify barriers to their implementation. We surveyed providers from academic and community practices regarding their currently implemented multidisciplinary care models, available resources, and perceived barriers using the Bladder Cancer Advocacy Network and the Genitourinary Medical Oncologists of Canada e-mail databases.
RESULTS: Of the 101 responding providers, most practiced at academic institutions in the United States (61%) or Canada (29%), and only 7% were from community practices. The most frequently used model was sequential visits on different days (57%), followed by sequential same-day (39%) and concurrent (1 visit with all providers; 22%) models. However, most practitioners preferred a multidisciplinary clinic involving sequential same-day (41%) or concurrent (26%) visits. The lack of clinic space (58%), funding (41%), staff (40%), and time (32%) were the most common barriers to implementing a multidisciplinary clinic.
CONCLUSION: Most surveyed practitioners at academic centers use some form of a multidisciplinary care model for patients with MIBC. The major barriers to more integrated multidisciplinary clinics were limited time and resources rather than a lack of provider enthusiasm. Future studies should incorporate patient preferences, further evaluate practice patterns in community settings, and assess their effects on patient outcomes.

PMID: 29289519 [PubMed - as supplied by publisher]

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Comparing Uniplanar and Multiaxial Pedicle Screws in the Derotation of Apical Vertebrae for Lenke V Adolescent Idiopathic Scoliosis (AIS): A Case Controlled Study.

Comparing Uniplanar and Multiaxial Pedicle Screws in the Derotation of Apical Vertebrae for Lenke V Adolescent Idiopathic Scoliosis (AIS): A Case Controlled Study.

World Neurosurg. 2017 Dec 28;:

Authors: Lin T, Li T, Jiang H, Ma J, Zhou X

Abstract
OBJECTION: To compare the use of uniplanar and multiaxial pedicle screws in terms of their effects on the apical vertebral derotation efficiency in Lenke V AIS patients.
METHODS: A retrospective study was performed, and Lenke V AIS patients with uniplanar pedicle screws (Group I) and multiaxial pedicle screws (Group II) were collected from Jan 2013 to Dec 2015. The grade of the apical vertebral rotation was evaluated before and after surgery using the Nash-Moe and Upasani methods, respectively. The SRS-22 scale was also used to evaluate the satisfaction of the patients.
RESULTS: There were no significant differences in terms of age, duration of follow up, correction ratio, and preoperative level of apical rotation between both groups (p<0.05). Group I indicated better apical vertebral derotation than Group II (0 level: 10.5% versus 2.3%, I level: 71.1% versus 38.6%, II level: 18.4% versus 59.1%; p=0.001). The progression group showed lower bone maturity (p<0.0001, OR=52.0, 95%CI: 6.3∼430.7) in Group I, and similar results were observed in Group II (p=0.057, OR=12.3, 95%CI: 1.3∼121.3). Patients from Group I showed better satisfaction than those from Group II based on the SRS-22 scores (p<0.05).
CONCLUSION: Both types of pedicle screws could provide effective correction, but the uniplanar pedicle screw was better for derotation of vertebrae and provided patients with better satisfaction. Skeleton immaturity was positively correlated with the progression of vertebral rotation after surgery.

PMID: 29289805 [PubMed - as supplied by publisher]

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Endovascular Management of Multiple Dysplastic Aneurysms in a Young Male With an Unknown Underlying Etiology: A Case Report and Review of the Literature.

Endovascular Management of Multiple Dysplastic Aneurysms in a Young Male With an Unknown Underlying Etiology: A Case Report and Review of the Literature.

World Neurosurg. 2017 Dec 28;:

Authors: Scullen T, Mathkour M, Lockwood J, Ott L, Medel R, Dumont AS, Amenta PS

Abstract
BACKGROUND: Intracranial aneurysms (IA) are the leading cause of non-traumatic subarachnoid hemorrhage and are most commonly associated with the anterior cerebral artery (ACA) and anterior communicating artery complex. We describe the presentation and management of a 27-year-old male with concurrent bilateral A1-2 junction aneurysms and fusiform intraorbital ophthalmic artery (OA) aneurysms.
CASE DESCRIPTION: A 27-year-old male with no past medical history presented with three months of headaches. Imaging reveled a large dysplastic left A1-2 junction aneurysm and a smaller saccular right A1-2 junction aneurysm, with potentially adherent domes. Two fusiform aneurysms of the intraorbital segment of the left OA were also identified. The patient underwent coil-assisted Pipeline embolization of the left A1-A2 aneurysm, with complete obliteration and reconstitution of the normal parent vessel. The patient underwent coil embolization of the right A1-2 aneurysm 3 weeks later, and was found to have grown significantly at the time of treatment. Three-month follow-up demonstrated spontaneous resolution of the OA aneurysms, persistent obliteration of the left aneurysm and significant recurrence of the right aneurysm, which was treated with stent-assisted coil embolization. A second recurrence three months later was successfully treated with repeat coiling. At the time of this treatment, the patient was also found to have two de novo distal middle cerebral artery (MCA) and ACA dysplastic aneurysms which were not treated. Follow up angiography 6 weeks later demonstrated stable complete obliteration of the right A1-2 aneurysm and interval complete resolution of the dysplastic MCA aneurysm. The distal ACA aneurysm was observed to have minimally increased in size, however, the parent vessel showed signs of interval partial thrombosis with contrast stasis within the aneurysm. This final aneurysm is currently being followed with serial imaging. The patient remains neurologically intact with complete resolution of his headaches.
CONCLUSION: We present a young male with no past medical history who presented with multiple dysplastic aneurysms. Successful staged endovascular intervention resulted in obliteration of aneurysms with spontaneous obliteration of the intraorbital OA aneurysms observed at three months. We present this case to review the multiple challenges of managing complex ACA aneurysms and to highlight the utility of endovascular intervention in their treatment.

PMID: 29289804 [PubMed - as supplied by publisher]

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Application of a rubber band with hooks on both ends for vagus nerve stimulator implantation.

Application of a rubber band with hooks on both ends for vagus nerve stimulator implantation.

World Neurosurg. 2017 Dec 28;:

Authors: Hosoyama H, Hanaya R, Otsubo T, Sato M, Kashida Y, Sugata S, Katagiri M, Iida K, Arita K

Abstract
BACKGROUND: Vagus nerve stimulation (VNS) is a valuable therapeutic option for many types of drug-resistant epilepsy. Muscle hooks and carotid endarterectomy rings have been used for cervical delamination preceding the implantation of stimulation electrodes. The attachment on both sides of a rubber band of Kamiyama-style hanging needles, as are used for scalp and dural retraction during craniotomy, yields a useful tool for VNS implantation. Here we report our experience with this method.
METHODS: We present our method using a rubber band-plus-hooks and a review of 21 consecutive patients who underwent VNS implantation using our rubber band-plus-hooks method.
RESULTS: None of the 21 patients experienced intra- or perioperative complications. Hooks placed in connective tissue around the common carotid artery and jugular vein raised the vagus nerve by elevating the carotid sheath. A single surgeon was able to perform all cervical manipulations under a surgical microscope; the average operation time in this series of 21 patients was 137 min.
CONCLUSIONS: The use of hooks attached to both sides of a rubber band rendered VNS implantation safer by lifting the vagus nerve and standardizing the procedure.

PMID: 29289803 [PubMed - as supplied by publisher]

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Contemporary Patterns of Multidisciplinary Care in Patients With Muscle-invasive Bladder Cancer.

Contemporary Patterns of Multidisciplinary Care in Patients With Muscle-invasive Bladder Cancer.

Clin Genitourin Cancer. 2017 Dec 06;:

PMID: 29289519 [PubMed - as supplied by publisher]

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Sialendoscopy in treatment of adult chronic recurrent parotitis without sialolithiasis.

Sialendoscopy in treatment of adult chronic recurrent parotitis without sialolithiasis.

Eur Arch Otorhinolaryngol. 2017 Dec 30;:

Authors: Jokela J, Haapaniemi A, Mäkitie A, Saarinen R

PMID: 29290052 [PubMed - as supplied by publisher]

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Decreased plasma DEK Oncogene Levels Correlate with p16-Negative Disease and Advanced Tumor Stage in a Case-Control Study of Patients with Head and Neck Squamous Cell Carcinoma.

Decreased plasma DEK Oncogene Levels Correlate with p16-Negative Disease and Advanced Tumor Stage in a Case-Control Study of Patients with Head and Neck Squamous Cell Carcinoma.

Transl Oncol. 2017 Dec 28;11(1):168-174

Authors: Wise-Draper T, Sendilnathan A, Palackdharry S, Pease N, Qualtieri J, Butler R, Sadraei NH, Morris JC, Patil Y, Wilson K, Mark J, Casper K, Takiar V, Lane A, Privette Vinnedge L

Abstract
Head and neck cancer (HNC) remains the sixth most common malignancy worldwide and survival upon recurrence and/or metastasis remains poor. HNSCC has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV) has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the DEK oncogenic protein, which was previously detected in the urine of patients with bladder cancer and is known to be secreted by immune cells such as macrophages. Here, we investigated if DEK could be detected in human plasma and if DEK levels correlated with clinical and pathological variables of HNSCC. Plasma was separated from the peripheral blood of newly diagnosed, untreated HNSCC patients or age-matched normal healthy controls and analyzed for DEK protein using ELISA. Plasma concentrations of DEK protein were lower in p16-negative tumors compared to both normal controls and patients with p16-positive tumors. Patients with lower plasma concentrations of DEK were also more likely to have late stage tumors and a lower white blood cell count. Contrary to previously published work demonstrating a poor prognosis with high intratumoral DEK levels, we show for the first time that decreased concentrations of DEK in patient plasma correlates with poor prognostic factors, including HPV-negative status as determined by negative p16 expression and advanced tumor stage.

PMID: 29289845 [PubMed - as supplied by publisher]

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Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.

Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.

EBioMedicine. 2017 Dec 20;:

Authors: Kamei S, Fujikawa H, Nohara H, Ueno-Shuto K, Maruta K, Nakashima R, Kawakami T, Matsumoto C, Sakaguchi Y, Ono T, Suico MA, Boucher RC, Gruenert DC, Takeo T, Nakagata N, Li JD, Kai H, Shuto T

Abstract
Airway mucus hyperproduction and fluid imbalance are important hallmarks of cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians. Dysregulated expression and/or function of airway ion transporters, including cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC), have been implicated as causes of CF-associated mucus hypersecretory phenotype. However, the contributory roles of other substances and transporters in the regulation of CF airway pathogenesis remain unelucidated. Here, we identified a novel connection between CFTR/ENaC expression and the intracellular Zn2+ concentration in the regulation of MUC5AC, a major secreted mucin that is highly expressed in CF airway. CFTR-defective and ENaC-hyperactive airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the zinc importer ZIP2/SLC39A2 (ΔC-ZIP2), which lacks the C-terminal domain. Importantly, ΔC-ZIP2 levels correlated inversely with wild-type ZIP2 and intracellular Zn2+ levels. Moreover, the splice switch to ΔC-ZIP2 as well as decreased expression of other ZIPs caused zinc deficiency, which is sufficient for induction of MUC5AC; while ΔC-ZIP2 expression per se induced ENaC expression and function. Thus, our findings demonstrate that the novel splicing switch contributes to CF lung pathology via the novel interplay of CFTR, ENaC, and ZIP2 transporters.

PMID: 29289532 [PubMed - as supplied by publisher]

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On the studies of time periods in head and neck cancer diagnosis and treatment.

On the studies of time periods in head and neck cancer diagnosis and treatment.

Oral Oncol. 2017 Dec 27;:

Authors: Varela-Centelles P, García-Martín JM, Seoane-Romero J

PMID: 29289443 [PubMed - as supplied by publisher]

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Effect of carrier bandwidth on integration of simulations of acoustic and electric hearing within or across ears.

Effect of carrier bandwidth on integration of simulations of acoustic and electric hearing within or across ears.

J Acoust Soc Am. 2017 Dec;142(6):EL561

Authors: Fu QJ, Galvin JJ, Wang X

Abstract
Differences in current spread and/or spread of excitation may differently affect integration of acoustic and electric hearing within (electric-acoustic stimulation, or EAS) or across ears (bimodal). In this study, vowel recognition was measured in normal-hearing subjects listening to simulations of cochlear implant (CI), EAS, and bimodal listening. Residual acoustic hearing was limited between 0.1 and 0.6 kHz. The carrier bandwidth in the CI simulations was varied across carriers: broad-band noise, narrow-band noise, and sine waves. Results showed that reducing the bandwidth (and the inherent noise fluctuations) in the CI simulations significantly affected CI-only and bimodal performance, but not EAS performance.

PMID: 29289073 [PubMed - in process]

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Integrating coaches into the national training programme: A modern approach to surgical supervision.

Integrating coaches into the national training programme: A modern approach to surgical supervision.

Int J Surg. 2017 Dec 28;:

Authors: Ahmed F, Sheriff IHN, Al-Alusi M, Ahmed N, Lasoye T

PMID: 29289678 [PubMed - as supplied by publisher]

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Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases.

Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases.

Behav Brain Res. 2017 Dec 28;:

Authors: Morris G, Berk M, Carvalho AF, Maes M, Walker AJ, Puri BK

Abstract
Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter-1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q10, iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N-acetylcysteine.

PMID: 29289598 [PubMed - as supplied by publisher]

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Evaluation of the Supraglottic and Subglottic Activities Including Acoustic Assessment of the Opera-Chant Singers.

Evaluation of the Supraglottic and Subglottic Activities Including Acoustic Assessment of the Opera-Chant Singers.

J Voice. 2017 Dec 28;:

Authors: Petekkaya E, Yücel AH, Sürmelioğlu Ö

Abstract
Opera and chant singers learn to effectively use aerodynamic components by breathing exercises during their education. Aerodynamic components, including subglottic air pressure and airflow, deteriorate in voice disorders. This study aimed to evaluate the changes in aerodynamic parameters and supraglottic structures of men and women with different vocal registers who are in an opera and chant education program. Vocal acoustic characteristics, aerodynamic components, and supraglottic structures were evaluated in 40 opera and chant art branch students. The majority of female students were sopranos, and the male students were baritone or tenor vocalists. The acoustic analyses revealed that the mean fundamental frequency was 152.33 Hz in the males and 218.77 Hz in the females. The estimated mean subglottal pressures were similar in females (14.99 cmH2O) and in males (14.48 cmH2O). Estimated mean airflow rates were also similar in both groups. The supraglottic structure compression analyses revealed partial anterior-posterior compressions in 2 tenors and 2 sopranos, and false vocal fold compression in 2 sopranos. Opera music is sung in high-pitched sounds. Attempts to sing high-pitched notes and frequently using register transitions overstrain the vocal structures. This intense muscular effort eventually traumatizes the vocal structures and causes supraglottic activity.

PMID: 29289411 [PubMed - as supplied by publisher]

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Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound.

Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound.

Eur J Med Chem. 2017 Dec 16;144:572-581

Authors: Lara LS, Moreira CS, Calvet CM, Lechuga GC, Souza RS, Bourguignon SC, Ferreira VF, Rocha D, Pereira MCS

Abstract
The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC50 values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity.

PMID: 29289882 [PubMed - as supplied by publisher]

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Brevilin A induces apoptosis and autophagy of colon adenocarcinoma cell CT26 via mitochondrial pathway and PI3K/AKT/mTOR inactivation.

Brevilin A induces apoptosis and autophagy of colon adenocarcinoma cell CT26 via mitochondrial pathway and PI3K/AKT/mTOR inactivation.

Biomed Pharmacother. 2017 Dec 28;98:619-625

Authors: You P, Wu H, Deng M, Peng J, Li F, Yang Y

Abstract
Brevilin A is a sesquiterpene lactone isolated from Centipeda minima and possesses inhibitory effects on proliferation of various tumor cells. In this study, Brevilin A inhibitory effect on proliferation and its molecular mechanism of action were investigated both in vivo and in vitro in colon adenocarcinoma CT26 cells. The results indicated that the inhibitory effect of Brevilin A in CT26 proliferation was dose-dependent and this effect was due to apoptosis. Furthermore, Brevilin A increased ROS levels, decreased mitochondrial membrane potential (MMP) and induced apoptosis of CT26 cell in a dose-dependent manner. Apoptosis induced by Brevilin A was higher than that induced by adriamycin under the same dose. Cleaved-caspase-8, cleaved-caspase-9 and cleaved-caspase-3 were up-regulated after Brevilin A treatment, together with an increase of Bax protein expression, while Bcl-2 was reduced. Further investigation revealed that Brevilin A inhibited the phosphorylation of PI3K, AKT and mTOR and promoted the expressions of autophagy-related proteins LC3-II, Beclin1 and Atg5 and consequent formation of autophagosomes, whereas 3-methyladenine (3-MA), a type III PI3K inhibitor, inhibited autophagosomes formation induced by Brevilin A. In vivo investigation suggested that Brevilin A significantly inhibited the growth of CT26 tumor compared to adriamycin and concurrently promoted the expressions of LC3-II and cleaved-caspase-3 in tumor tissues. Our results demonstrated that the anti-tumor activity of Brevilin A was mainly achieved by the induction of cell apoptosis and autophagy, suggesting a promising potential as antitumor drug against colon adenocarcinoma.

PMID: 29289836 [PubMed - as supplied by publisher]

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The size of zinc oxide nanoparticles controls its toxicity through impairing autophagic flux in A549 lung epithelial cells.

The size of zinc oxide nanoparticles controls its toxicity through impairing autophagic flux in A549 lung epithelial cells.

Toxicol Lett. 2017 Dec 28;:

Authors: Wang B, Zhang J, Chen C, Xu G, Qin X, Hong Y, Bose DD, Qiu F, Zou Z

Abstract
Zinc oxide nanoparticles (ZnONPs) widely used in various products, have been concerned with its impact on human health, in particular, on the risk of pulmonary toxicity. Our previous study indicated that ZnONPs could harness autophagy and impair the autophagic flux, which was positively linked to ZnONPs-induced toxicity. The objective of this study was to investigate whether ZnONPs-induced impairment of autophagic flux and cell death in lung epithelial cells is related to the size of ZnONPs. We demonstrate that ZnONPs with the average size of 50 nm could induce toxic effects in A549 lung epithelial cells, including accumulation of autophagosomes (the elevation of LC3B-II/LC3B-I ratio), impaired autophagic flux (the increase of p62 expression), the release of intracellular zinc ions (the increase of FluoZin-3 signal and ZnT1 mRNA expression), mitochondrial damage (the decrease of TMRE signal), lysosomal dysfunction (the aberrant expression of LAMP-2), oxidative stress (the increase of DCFH-DA signal and HO-1 expression) and cell death. Interestingly, ZnONPs with the average size of 200 nm failed to induce autophagy-mediated toxicity. Taken together, our results indicate that the size of ZnONPs is closely correlated with its toxicity, which is probably mediated by induction of impaired autophagic flux. This finding provides an insight into better understating of ZnONPs-associated toxicity, and mitigating the risk to humans and allowing the safer application.

PMID: 29289694 [PubMed - as supplied by publisher]

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Monitoring autophagic flux using p62/SQSTM1 based luciferase reporters in glioma cells.

Monitoring autophagic flux using p62/SQSTM1 based luciferase reporters in glioma cells.

Exp Cell Res. 2017 Dec 28;:

Authors: Min Z, Ting Y, Mingtao G, Xiaofei T, Dong Y, Chenguang Z, Wei D

Abstract
Autophagy is a highly dynamic process characterized with the term of autophagic flux. In the present study, we developed a quantifiable luciferase reporter system to measure the capacity as well as the dynamics of autophagic flux. Briefly, a luciferase variant of Luc2p was fused with p62/SQSTM1 or its UBA domain deletion mutant (p62ΔU) and transfected into cells. The expressed Luc2p-p62 fusion protein was primarily degraded via autophagy, while Luc2p-p62ΔU was employed as a normalization control due to its resistance to autophagic degradation. The luciferase activity of the lysates from two parallel populations of glioma cells expressing either Luc2p-p62 or Luc2p-p62ΔU was determined and the ratio of Luc2p-p62ΔU/Luc2p-p62 was used to assay the autophagic flux. By this approach, the induction of autophagy was manifested as an increased Luc2p-p62ΔU/Luc2p-p62 ratio, which could be neutralized by autophagy inhibitors or knockdown of ATG5. The performance of our autophagic flux detection system was comparable to a recently reported GFP-LC3-RFP-LC3ΔG probe. We tested the system in TMZ treated glioma cells, and found that coadministration of chloroquine to attenuate cellular autophagic flux significantly improved the TMZ efficacy by triggering more early apoptosis. Collectively, our luciferase-based autophagic flux assay may serve as a useful alternative yet sensitive method for autophagic flux detection in tumor cells.

PMID: 29289595 [PubMed - as supplied by publisher]

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Nutrient excess and autophagic deficiency: explaining metabolic diseases in obesity.

Nutrient excess and autophagic deficiency: explaining metabolic diseases in obesity.

Metabolism. 2017 Dec 28;:

Authors: van Niekerk G, duToit A, Loos B, Engelbrecht AM

Abstract
Over-nutrition and a sedentary lifestyle are the driving forces behind the development of metabolic diseases. Conversely, caloric restriction and exercise have proven to be the most effective strategies in combating metabolic diseases. Interestingly, exercise and caloric restriction share a common feature: both represent a potent mechanism for upregulating autophagy. Autophagy is rapidly induced by nutrient deprivation, and conversely, inactivated by amino acids as well as growth factors (e.g. insulin). Here, we review evidence demonstrating that autophagy may indeed be attenuated in metabolic tissue such as liver, muscle, and adipose, in the context of obesity. We also highlight the mechanistic basis by which defective autophagy may contribute to the manifestation of metabolic diseases. This includes a compromised ability of the cell to perform quality control on the mitochondrial matrix, since autophagy plays a pivotal role in the degradation of defective mitochondria. Similarly, autophagy also plays an indispensable role in the clearance of protein aggregates and redundant large protein platforms such as inflammasomes. Autophagy might also play a key role in the metabolism of endotoxins, implicating the importance of autophagy in the pathogenesis of metabolic endotoxemia. These observations underpin an unprecedented role of autophagy in the manifestation of obesity-induced metabolic derangement.

PMID: 29289514 [PubMed - as supplied by publisher]

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Κυριακή 31 Δεκεμβρίου 2017

Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together-a real life study.

Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together-a real life study.

Rhinology. 2017 Dec 30;:

Authors: Bidder T, Sahota J, Rennie C, Lund VJ, Robinson DS, Kariyawasam HH

Abstract
INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma often coexist and thus treating both with one intervention is an attractive strategy.
OBJECTIVE: To prospectively evaluate whether treatment with the monoclonal antibody against IgE Omalizumab for severe allergic asthma also effectively treats co-existent CRSwNP.
METHODS: SNOT-22 and the ACQ-7 scores were recorded at 4 and 16 weeks of treatment in a cohort of patients with both CRSwNP and severe refractory allergic asthma treated with Omalizumab (n=13) according to UK guidelines for their severe asthma. SNOT-22 in a surgery only treated CRSwNP with asthma group (n=24) was compared.
RESULTS: Rapid improvement was seen at 4 weeks and 16 weeks of treatment in both CRSwNP and asthma control. The improvement in CRSwNP with Omalizumab was similar to that seen in a group of patients who received upper airway surgery.
CONCLUSION: Omalizumab treatment for severe allergic asthma also improves co-existent CRSwNP. Further clinical studies of current and emerging biological agents for severe asthma should include upper airway outcomes. These agents may be effective for severe CRSwNP and comparative studies with surgery are warranted.

PMID: 29288573 [PubMed - as supplied by publisher]

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Functional anatomy of the nasal bones and adjacent structures. Consequences for nasal surgery.

Functional anatomy of the nasal bones and adjacent structures. Consequences for nasal surgery.

Rhinology. 2017 Dec 29;:

Authors: Popko M, Verlinde-Schellekens SAMW, Huizing EH, Bleys RLAW

Abstract
The periosteum of the nasal bones, the periosteal-perichondrial nasal envelope, and the cartilaginous support of the bony vault were studied in serial coronal sections of four human cadaver noses. To differentiate between the various tissue components, the sections were stained according to Mallory-Cason and Verhoeff-Van Gieson stain. The results demonstrated: 1. the presence of clearly distinguishable layers of the periosteum covering the nasal bones; 2. the presence of a continuous periosteal-perichondrial covering of the bony and cartilaginous nasal vaults; 3. the way the cartilaginous support of the bony vault is constructed. The findings described in the present study may have clinical relevance in nasal surgery.

PMID: 29286059 [PubMed - as supplied by publisher]

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