OtoRhinoLaryngology by Alexandros G.Sfakianakis

Τρίτη 2 Ιανουαρίου 2018

upper respiratory tract infection; +22 new citations

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upper respiratory tract infection

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CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis.

CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis.

Dev Cell. 2017 Dec 27;:

Authors: Smith MD, Harley ME, Kemp AJ, Wills J, Lee M, Arends M, von Kriegsheim A, Behrends C, Wilkinson S

Abstract
Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy. The CCPG1 gene is inducible by the unfolded protein response and thus directly links ER stress to ER-phagy. In vivo, CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas. Thus, via identification of this autophagy protein, we describe an unexpected molecular mechanism of ER-phagy and provide evidence that this may be physiologically relevant in ER luminal proteostasis.

PMID: 29290589 [PubMed - as supplied by publisher]

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Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy.

Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy.

Theranostics. 2018;8(1):141-155

Authors: Rojas JD, Lin F, Chiang YC, Chytil A, Chong DC, Bautch VL, Rathmell WK, Dayton PA

Abstract
Metastatic clear-cell renal cell carcinoma (ccRCC) affects thousands of patients worldwide each year. Antiangiogenic therapy has been shown to have beneficial effects initially, but resistance is eventually developed. Therefore, it is important to accurately track the response of cancer to different therapeutics in order to appropriately adjust the therapy to maximize efficacy. Change in tumor volume is the current gold standard for determining efficacy of treatment. However, functional variations can occur much earlier than measurable volume changes. Contrast-enhanced ultrasound (CEUS) is an important tool for assessing tumor progression and response to therapy, since it can monitor functional changes in the physiology. In this study, we demonstrate how ultrasound molecular imaging (USMI) can accurately track the evolution of the disease and molecular response to treatment. Methods A cohort of NSG (NOD/scid/gamma) mice was injected with ccRCC cells and treated with either the VEGF inhibitor SU (Sunitinib malate, Selleckchem, TX, USA) or the Notch pathway inhibitor GSI (Gamma secretase inhibitor, PF-03084014, Pfizer, New York, NY, USA), or started on SU and later switched to GSI (Switch group). The therapies used in the study focus on disrupting angiogenesis and proper vessel development. SU inhibits signaling of vascular endothelial growth factor (VEGF), which is responsible for the sprouting of new vasculature, and GSI inhibits the Notch pathway, which is a key factor in the correct maturation of newly formed vasculature. Microbubble contrast agents targeted to VEGFR-2 (VEGF Receptor) were delivered as a bolus, and the bound agents were imaged in 3D after the free-flowing contrast was cleared from the body. Additionally, the tumors were harvested at the end of the study and stained for CD31. Results The results show that MI can detect changes in VEGFR-2 expression in the group treated with SU within a week of the start of treatment, while differences in volume only become apparent after the mice have been treated for three weeks. Furthermore, USMI can detect response to therapy in 92% of cases after 1 week of treatment, while the detection rate is only 40% for volume measurements. The amount of targeting for the GSI and Control groups was high throughout the duration of the study, while that of the SU and Switch groups remained low. However, the amount of targeting in the Switch group increased to levels similar to those of the Control group after the treatment was switched to GSI. CD31 staining indicates significantly lower levels of patent vasculature for the SU group compared to the Control and GSI groups. Therefore, the results parallel the expected physiological changes in the tumor, since GSI promotes angiogenesis through the VEGF pathway, while SU inhibits it. Conclusion This study demonstrates that MI can track disease progression and assess functional changes in tumors before changes in volume are apparent, and thus, CEUS can be a valuable tool for assessing response to therapy in disease. Future work is required to determine whether levels of VEGFR-2 targeting correlate with eventual survival outcomes.

PMID: 29290798 [PubMed - in process]

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Opportunistic salpingectomy at benign gynecological surgery for reducing ovarian cancer risk: a 10-year single centre experience from China and a literature review.

Opportunistic salpingectomy at benign gynecological surgery for reducing ovarian cancer risk: a 10-year single centre experience from China and a literature review.

J Cancer. 2018;9(1):141-147

Authors: Chen Y, Du H, Bao L, Liu W

Abstract
Current evidences indicate that the fallopian tube plays a major role in the pathogenesis of epithelial ovarian cancer (EOC). Salpingectomy represents a novel and potentially effective risk-reducing option. In this study, there were 1822 patients diagnosed and treated for EOC or primary peritoneal cancer (PPC) at Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital from January 1, 2007 to April 30, 2017. Among them, 198 patients with a history of gynecological surgery because of benign diseases were enrolled to analyze further. Using 1:2 case-control study, we found that the incidence of EOC was significantly decreased in the population with salpingectomy, compared to women with fallopian tube reserved (P<0.05). At the same period, there were 4339 patients receiving opportunistic salpingectomy in our centre because of benign gynecological diseases. The results showed the rate of bilateral salpingectomy was annually increased from 2007 to 2017 (22.02% to 60.22%), which showed approximately threefold increase in a decade. In general, factors affecting the rate of salpingectomy included age, child number, menopause or not, marital status, educational status, income status, and with or without family history of tumor. Therefore, based on ten years experiences from our centre, it is recommended that physician should discuss with appropriate patients to perform opportunistic bilateral salpingectomy at the time of receiving benign gynecological surgery for preventing ovarian cancer. Moreover, the prospective, large scale and multi-centre studies to evaluate the safety and efficacy of salpingectomy as a preventive strategy for ovarian cancer warrant to conduct in the future.

PMID: 29290779 [PubMed]

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Hepatic arterial infusion in the management of colorectal cancer liver metastasis: Current and future perspectives.

Hepatic arterial infusion in the management of colorectal cancer liver metastasis: Current and future perspectives.

Dig Liver Dis. 2017 Dec 14;:

Authors: Chapelle N, Matysiak-Budnik T, Douane F, Metairie S, Rougier P, Touchefeu Y

Abstract
The technique of hepatic arterial infusion (HAI) for the treatment of liver metastases from colorectal cancer has been developed over more than 30 years. Although the indications and protocols for this technique have evolved with time, HAI is not routinely performed in clinical practice. Studies have been heterogeneous, with different regimens of intra-arterial drugs, associated or not with systemic chemotherapy, and with unconvincing outcomes. Technical difficulties for catheter placement have limited the implementation of this method in routine practice. The aim of this review is to present recent studies, highlighting technical improvements and promising combinations of oxaliplatin-based HAI with systemic treatments. HAI is being investigated in both the metastatic setting - in the first line and beyond - and in the adjuvant setting, and we will discuss its potential place in current and future patient management.

PMID: 29290599 [PubMed - as supplied by publisher]

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Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions.

Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions.

Lung Cancer. 2018 Jan;115:12-20

Authors: Soo RA, Lim SM, Syn NL, Teng R, Soong R, Mok TSK, Cho BC

Abstract
Major advances with the development of epidermal growth factor receptor tyrosine kinase inhibitors and immune check-point inhibitors have ushered in a new era in lung cancer therapy. Whilst pre-clinical studies suggest EGFR-driven NSCLC inhibit antitumor immunity through the activation of the PD-1/PD-L1 pathway, epidemiology studies suggest EGFR mutant NSCLC are more likely to have decreased PD-L1 expression. The superiority of single agent PD-1/PD-L1 inhibitors over docetaxel in pre-treated EGFR mutant NSCLC appears to be moderated. Several mechanisms for a poor response to immune checkpoint have been proposed including a lower tumor mutation burden, and an uninflamed and immunosuppressive tumor microenvironment. Predictive biomarkers to PD-1/PD-L1 inhibitors sensitivity in patients with EGFR mutations are required. The role of EGFR TKI in combination with an immune checkpoint inhibitor is currently being investigated intensively in multiple clinical trials and outcomes from these trials are immature and the optimal sequence, schedule and dosing remains to be determined. A careful evaluation will be required in view of the increased toxicities reported in some of the early studies of combination therapy.

PMID: 29290252 [PubMed - in process]

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A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams.

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A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams.

Phys Med Biol. 2017 Jul 07;62(13):5531-5555

Authors: Masood U, Cowan TE, Enghardt W, Hofmann KM, Karsch L, Kroll F, Schramm U, Wilkens JJ, Pawelke J

Abstract
Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

PMID: 28609301 [PubMed - indexed for MEDLINE]

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Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.

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Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.

Pharmacol Ther. 2017 Jun;174:1-21

Authors: Lee DH

Abstract
The discovery of epidermal growth factor receptor (EGFR) activating mutations in non-small cell lung cancer (NSCLC) and the success story of EGFR tyrosine kinases inhibitors (TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. As a result, EGFR TKI therapy, including gefitinib, erlotinib and afatinib, has become the standard therapy for NSCLC patients with EGFR activating mutation as first-line therapy. However, most patients inevitably progress despite initial dramatic and rapid response to EGFR TKIs and therefore during the last decade, a lot of efforts have been made to identify and overcome various resistance mechanisms. Fortunately, T790M secondary mutation, the main resistance mechanism, can be overcome by newly developed third-generation EGFR TKIs, such as osimertinib, while most combination trials trying to overcome resistance mechanisms other than T790M mutation have failed so far. To make it worse, spatial and temporal tumor heterogeneity and clonal selection or evolution are also identified in EGFR mutant NSCLC tumors. Nevertheless, advance of comprehensive and more sensitive molecular diagnostics and monitoring technology, such as next-generation sequencing and dynamic monitoring technology using circulating biomarker and development of new cancer medicine with different mechanisms from EGFR TKIs, especially immune checkpoint inhibitors, might affect or change the treatment paradigm of EGFR mutant NSCLC in the near future.

PMID: 28167215 [PubMed - indexed for MEDLINE]

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Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening.

Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening.

Bioorg Med Chem Lett. 2017 Dec 13;:

Authors: Zou F, Pusch S, Hua J, Ma T, Yang L, Zhu Q, Xu Y, Gu Y, von Deimling A, Zha X

Abstract
IDH1 mutation (mIDH1) occurs in 20-30% of gliomas and is a promising target for the cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.

PMID: 29290542 [PubMed - as supplied by publisher]

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Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling.

Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling.

Oncotarget. 2017 Dec 05;8(63):107076-107088

Authors: Shang YY, Yao M, Zhou ZW, Jian-Cui, Li-Xia, Hu RY, Yu YY, Qiong-Gao, Biao-Yang, Liu YX, Dang J, Zhou SF, Nan-Yu

Abstract
We investigated the efficacy of Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, in melanoma. We found that ALS exerts anti-proliferative, pro-apoptotic, and pro-autophagic effects on A375 and skmel-5 melanoma cells by inhibiting p38 MAPK signaling. SB202190, a p38 MAPK-selective inhibitor, enhanced ALS-induced apoptosis and autophagy in both cell lines. ALS induced cell cycle arrest in melanoma cells through activation of the p53/p21/cyclin B1 pathway. Knockdown of p38 MAPK enhanced ALS-induced apoptosis and reduced ALS-induced autophagy. Inhibition of autophagy sensitized melanoma cells to ALS-induced apoptosis. These data indicate ALS is a potential therapeutic agent for melanoma.

PMID: 29291012 [PubMed]

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The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling.

The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling.

Oncotarget. 2017 Dec 05;8(63):106753-106763

Authors: Cheng Z, Yi Y, Xie S, Yu H, Peng H, Zhang G

Abstract
Previous reports have shown that active JAK2 contributes to T cell acute lymphoblastic leukaemia (T-ALL) development and that JAK inhibitors may be a potential treatment for T-ALL. In the current study, the JAK2 inhibitor TG101209 was used to treat T-ALL cell lines and primary T-ALL cells. The effects of TG101209 on T-ALL cells were determined, and the signaling proteins related to cell growth, apoptosis and autophagy were analysed. The results indicated that TG101209 significantly inhibited T-ALL cell proliferation and induced cell apoptosis in a dose-dependent manner. The mechanisms involved the suppression of the JAK2-STAT signaling pathway and activation of apoptosis or autophagy. Additionally, a JAK2 gene copy gain (FISH) and up-regulated JAK2, LC3 and Beclin1 expression (western blotting) were observed in T-ALL samples compared with healthy controls, which implied that JAK2 is a target for T-ALL treatment. TG101209 initiated apoptosis and autophagy in T-ALL cells; therefore, this JAK2 inhibitor may be a potential drug or alternative therapy for T-ALL.

PMID: 29290986 [PubMed]

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Exacerbation of diabetic cardiac hypertrophy in OVE26 mice by angiotensin II is associated with JNK/c-Jun/miR-221-mediated autophagy inhibition.

Exacerbation of diabetic cardiac hypertrophy in OVE26 mice by angiotensin II is associated with JNK/c-Jun/miR-221-mediated autophagy inhibition.

Oncotarget. 2017 Dec 05;8(63):106661-106671

Authors: Qian LB, Jiang SZ, Tang XQ, Zhang J, Liang YQ, Yu HT, Chen J, Xu Z, Liu RM, Keller BB, Ji HL, Cai L

Abstract
Both diabetes and angiotensin II (Ang II) excess trigger cardiac remodeling and dysfunction, and diabetic cardiomyopathy. We hypothesized that cardiac hypertrophy associated with the development of diabetic cardiomyopathy is worsened by increased Ang II. Male type 1 diabetic OVE26 and wild-type mice were given Ang II (sc., 1.15 mg/kg, twice a day) for 14 days. Diabetes-induced cardiac dysfunction and hypertrophy was exacerbated by Ang II treatment as determined by echocardiography, wheat germ agglutinin staining and atrial natriuretic peptide. Ang II treatment dramatically exacerbated diabetes-caused decreased LC3-II, a marker of autophagy, and increased p62, an indicator of cytosolic protein clearance. Ang II treatment also augmented diabetes-associated increased phosphorylated levels of c-Jun, JNK, mTOR, and miR-221, and decreased of p27 expression, a direct target of miR-221. Chromatin immunoprecipitation assay showed that Ang II elevated c-Jun binding to the promoter of miR-221 in diabetic mice. These results suggest that Ang II accelerates cardiac hypertrophy in the early stage of murine diabetes, probably through activation of the JKN/c-Jun/miR-221 axis and inhibition of downstream autophagy. Therefore, inhibition of Ang II or miR-221 in diabetic individuals may be a potential approach for delaying the onset and/or reducing the severity of diabetic cardiomyopathy.

PMID: 29290979 [PubMed]

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Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy.

Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy.

Oncotarget. 2017 Dec 05;8(63):106233-106248

Authors: Fiesel FC, James ED, Hudec R, Springer W

Abstract
Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset Parkinson's disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy. While this pathway is generally accepted to occur upon chemical uncoupling of mitochondria, the (patho-) physiologic relevance has been questioned. However, few studies have indicated that PINK1 and Parkin are also activated upon accumulation of misfolded proteins in the mitochondrial lumen upon overexpression of ΔOTC (Ornithine transcarbamylase). Here, we used the mitochondrial targeted HSP90 inhibitor Gamitrinib-triphenylphosphonium (G-TPP), an anti-cancer agent, to chemically interfere with mitochondrial protein folding. G-TPP treatment induced PINK1 accumulation, ubiquitin phosphorylation at Ser65, Parkin activation and its recruitment to mitochondria was specific for mitochondrial HSP90 inhibition and largely independent of mitochondrial membrane depolarization. Mitophagy induction was observed by monitoring autophagy receptor recruitment and the mitoKeima reporter. Importantly, mitophagy was not only induced in cancer cells but also in primary human fibroblasts and thereof converted neurons. G-TPP treatment might represent a novel strategy to study PINK1 and Parkin-mediated mitochondrial quality control using a more physiologically relevant stress.

PMID: 29290944 [PubMed]

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PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.

PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.

Theranostics. 2018;8(1):109-123

Authors: Zeng J, Liu W, Fan YZ, He DL, Li L

Abstract
Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients. However, a substantial proportion of patients eventually becomes refractory due to drug resistance. The detailed mechanisms remain unclear. We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC. In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway. Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo. Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay. The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression. Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo. Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy. Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo. Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.

PMID: 29290796 [PubMed - in process]

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Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

J Cancer. 2018;9(1):117-128

Authors: Liu W, Song XL, Zhao SC, He M, Wang H, Chen Z, Xiang W, Yi G, Qi S, Liu Y

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7).
AIM: The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo.
MATERIALS AND METHODS: U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo.
RESULTS: Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo.
CONCLUSION: In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo.

PMID: 29290776 [PubMed]

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Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer.

Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer.

World J Gastroenterol. 2017 Dec 14;23(46):8109-8119

Authors: Sipos F, Székely H, Kis ID, Tulassay Z, Műzes G

Abstract
Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic beneﬁts could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.

PMID: 29290648 [PubMed - in process]

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Acid-Tolerant Monomeric GFP from Olindias formosa.

Acid-Tolerant Monomeric GFP from Olindias formosa.

Cell Chem Biol. 2017 Dec 23;:

Authors: Shinoda H, Ma Y, Nakashima R, Sakurai K, Matsuda T, Nagai T

Abstract
The fluorescent protein (FP) color palette has greatly contributed to the visualization of molecular and cellular processes. However, most FPs lose fluorescence at a pH lower than their neutral pKa (∼6), and this has hampered their application in acidic organelles (pH ∼4.5-6.0). Currently, several cyan- and red-colored acid-tolerant FPs are available; however, there are few reports of acid-tolerant green FPs (GFPs) that are practically applicable to bioimaging. Here, we developed the acid-tolerant monomeric GFP "Gamillus" from the jellyfish Olindias formosa, with excellent brightness, maturation speed, and photostability. Results from X-ray crystallography and point mutagenesis suggest that across a broad pH range the acid tolerance is attributed to stabilization of deprotonation in the chromophore phenyl ring by forming a unique trans configuration. We demonstrate that Gamillus can serve as a molecular tag suitable for imaging in acidic organelles through autophagy-mediated molecular tracking to lysosomes.

PMID: 29290624 [PubMed - as supplied by publisher]

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Cytotoxic effects of delphinidin in human osteosarcoma cells.

Cytotoxic effects of delphinidin in human osteosarcoma cells.

Acta Orthop Traumatol Turc. 2017 Dec 28;:

Authors: Lee DY, Park YJ, Hwang SC, Kim KD, Moon DK, Kim DH

Abstract
INTRODUCTION: The aim of this study was to evaluate whether delphinidin is cytoprotective or cytotoxic in osteosarcoma cell lines, and to elucidate the underlying mechanisms.
MATERIALS AND METHODS: The present study investigated whether apoptosis or autophagy is induced by delphinidin in human osteosarcoma cell lines. Delphinidin was used as the antioxidant, along with two autophagy inhibitors: 3-methyladenine and bafilomycin A1. Cell viability and known autophagic markers, such as LC3-II expression, were evaluated. Reactive oxygen species (ROS) formation and cell cycle analysis were also investigated.
RESULTS: Delphinidin showed concentration-dependent cytotoxicity to osteosarcoma cell. Delphinidin is closely associated with apoptotic cell death mechanisms and pathways related to ROS accumulation. In addition, we observed delphinidin-induced autophagosome formation and increasing levels of LC3-II conversion. However, in spite of delphinidin induced autophagy, the cytotoxic effects induced in the osteosarcoma cells may not be operating via autophagic cell death mechanisms.
CONCLUSIONS: Delphinidin compromises the cellular protective mechanisms by inhibiting autophagy, permitting ROS to accumulate and finally enhance apoptotic cell death. Our results indicate that delphinidin may play a critical role as a chemotherapeutic agent by preventing the development and progression of osteosarcoma cells.

PMID: 29290536 [PubMed - as supplied by publisher]

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Small Leucine-Rich Proteoglycans in Renal Inflammation: Two Sides of the Coin.

Small Leucine-Rich Proteoglycans in Renal Inflammation: Two Sides of the Coin.

J Histochem Cytochem. 2017 Oct 01;:22155417738752

Authors: Nastase MV, Janicova A, Roedig H, Hsieh LT, Wygrecka M, Schaefer L

Abstract
It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.

PMID: 29290137 [PubMed - as supplied by publisher]

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Corrigendum to "A mixed-effects model approach for the statistical analysis of vocal fold viscoelastic shear properties" [J. Mech. Behav. Biomed. Mater. 75 (2017) 477-485].

Corrigendum to "A mixed-effects model approach for the statistical analysis of vocal fold viscoelastic shear properties" [J. Mech. Behav. Biomed. Mater. 75 (2017) 477-485].

J Mech Behav Biomed Mater. 2017 Dec 29;79:114

Authors: Xu CC, Chan RW, Sun H, Zhan X

PMID: 29291464 [PubMed - as supplied by publisher]

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Ectopic Thymic Cyst of the Subglottis: Considerations for Diagnosis and Management.

Ectopic Thymic Cyst of the Subglottis: Considerations for Diagnosis and Management.

Ann Otol Rhinol Laryngol. 2017 Dec 01;:3489417749609

Authors: Ahmad I, Kirby P, Liming B

Abstract
OBJECTIVES: To share the diagnostic and management challenges created by an extremely rare airway lesion-the subglottic ectopic thymic cyst.
STUDY DESIGN: Case report and literature review.
METHODS: We review the presentation, management, and clinical course of an infant who presented with a subglottic mass that was histologically confirmed as a thymic cyst. A brief literature review supplements the case presentation Results: We present the third described case of an ectopic thymic cyst presenting as a subglottic mass. The differential diagnosis of subglottic masses in neonates consists primarily of subglottic hemangioma and mucous retention cysts. Otolaryngologists must be prepared for unexpected findings when dealing with critical airways. We compare the presentation and management of our patient with the 2 previously described cases. We propose an embryologic theory for the origin of these rare lesions.
CONCLUSIONS: An ectopic thymic cyst is a rare and unexpected cause of neonatal stridor. Management of pediatric airway lesions must allow for unexpected findings at the time of diagnostic and therapeutic endoscopy. The appropriate management of subglottic thymic cysts is poorly defined, but close surveillance for recurrence is mandatory.

PMID: 29291277 [PubMed - as supplied by publisher]

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Maxillofacial injuries among trauma patients undergoing head computerized tomography; A Ugandan experience.

Maxillofacial injuries among trauma patients undergoing head computerized tomography; A Ugandan experience.

Int J Crit Illn Inj Sci. 2017 Oct-Dec;7(4):236-240

Authors: Krishnan UC, Byanyima RK, Faith A, Kamulegeya A

Abstract
Aim: The aim of this study was to investigate epidemiological features of maxillofacial fractures within trauma patients who had head and neck computed tomography (CT) scan at the Mulago National referral hospital.
Methods: CT scan records of trauma patients who had head scans at the Department of Radiology over 1-year period were accessed. Data collected included sociodemographic factors, type and etiology of injury, and concomitant maxillofacial injuries.
Results: A total of 1330 trauma patients underwent head and neck CT scan in the 1-year study period. Out of these, 130 were excluded due to incomplete or unclear records and no evidence of injury. Of the remaining 1200, 32% (387) had maxillofacial fractures. The median age of the patients with maxillofacial fractures was 28 (range = 18-80) years and 18-27 age group was most common at 47.5%. Road traffic accidents constituted 49.1% of fractures. The single most affected isolated bone was the frontal bone (23%). The number of maxillofacial bones fractured was predicted by age group (df = 3 F = 5.358, P = 0.001), association with other fractures (df = 1 F = 5.317, P = 0.03).
Conclusions: Good matched case-control prospective studies are needed to enable us tease out the finer difference in the circumstances and pattern of injury if we are to design appropriate preventive measures.

PMID: 29291177 [PubMed]

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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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Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle - oligonucleotide nanoconstructs to head and neck cancer cells.

Dual radiosensitization and anti-STAT3 anti-proliferative strategy based on delivery of gold nanoparticle - oligonucleotide nanoconstructs to head and neck cancer cells.

Nanotheranostics. 2018;2(1):1-11

Authors: Zhang S, Gupta S, Fitzgerald TJ, Bogdanov AA

Abstract
Constitutively activated signal transducer and activator of transcription 3 (STAT3) factor is an important therapeutic target in head and neck cancer (HNC). Despite early promising results, a reliable systemic delivery system for STAT3- targeted oligonucleotide (ODN) drugs is still needed for future clinical translation of anti-STAT3 therapies. We engineered and tested a novel ODN duplex/gold nanoparticle (AuNP)-based system carrying a therapeutic STAT3 decoy (STAT3d) payload. This strategy is two-pronged because of the additive STAT3 antagonism and radiosensitizing properties of AuNP. The specificity to head and neck cancer cell surface was imparted by using a nucleolin aptamer (NUAP) that was linked to AuNP for taking the advantage of an aberrant presentation of a nuclear protein nucleolin on the cell surface. STAT3d and nucleolin aptamer constructs were independently linked to AuNPs via Au-S bonds. The synthesized AuNP constructs (AuNP-NUAP-STAT3d) exhibited internalization in cells that was quantified by using radiolabeled STAT3d. AuNP-NUAP-STAT3d showed radiosensitizing effect in human HNC FaDu cell culture experiments that resulted in an increase of cell DNA damage as determined by measuring γ-H2AX phosphorylation levels by flow cytometry. The radiosensitization study also demonstrated that AuNP-NUAP-STAT3d as well as STAT3d alone resulted in the efficient inhibition of A431 cell proliferation. While FaDu cells did not show instant proliferation inhibition after incubating with AuNP-NUAP-STAT3d, the cell DNA damage in these cells showed nearly a 50% increase in AuNP-NUAP-STAT3d group after treating with radiation. Compared with anti-EGFR humanized antibody (Cetuximab), AuNP-NUAP-STAT3d system had an overall stronger radiosensitization effect in both A431 and FaDu cells.

PMID: 29291159 [PubMed]

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Viral E6/E7 oncogene and cellular hexokinase 2 expression in HPV-positive cancer cell lines.

Viral E6/E7 oncogene and cellular hexokinase 2 expression in HPV-positive cancer cell lines.

Oncotarget. 2017 Dec 05;8(63):106342-106351

Authors: Hoppe-Seyler K, Honegger A, Bossler F, Sponagel J, Bulkescher J, Lohrey C, Hoppe-Seyler F

Abstract
Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. Cancer cells typically exhibit metabolic alterations which support their malignant growth. These include an enhanced rate of aerobic glycolysis ('Warburg effect') which in cancer cells is often linked to an increased expression of the rate-limiting glycolytic enzyme Hexokinase 2 (HK2). Intriguingly, recent studies indicate that the HPV E6/E7 oncogenes cause the metabolic reprogramming in HPV-positive cancer cells by directly upregulating HK2 expression. Notably, however, these results were obtained upon ectopic overexpression of E6/E7. Here, we investigated whether HK2 levels are affected by the endogenous E6/E7 amounts present in HPV-positive cancer cell lines. RNA interference analyses reveal that the sustained E6/E7 expression is critical to maintain HK2 expression levels in HeLa cells. Mechanistically, this effect is linked to the E6/E7-dependent upregulation of HK2-stimulatory MYC expression and the E6/E7-induced downregulation of the HK2-inhibitory micro(mi)RNA miR-143-3p. Importantly, however, a stimulatory effect of E6/E7 on HK2 expression was observed only in HeLa among a panel of 8 different HPV-positive cervical and head and neck cancer cell lines. Thus, whereas these results support the notion that E6/E7 can increase HK2 expression, they argue against the concept that the viral oncogenes, at endogenous expression levels, commonly induce the metabolic switch of HPV-positive cancer cells towards aerobic glycolysis by directly or indirectly stimulating HK2 expression.

PMID: 29290953 [PubMed]

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Common Paediatric Elbow Injuries.

Common Paediatric Elbow Injuries.

Open Orthop J. 2017;11:1380-1393

Authors: Hill CE, Cooke S

Abstract
Background: Paediatric elbow injuries account for a large proportion of childrens' fractures. Knowledge of common injuries is essential to understanding their assessment and correct management.
Methods: A selective literature search was performed and personal surgical experiences are reported.
Results: We have described the assessment and management of the five most common paediatric elbow injuries: supracondylar humeral fractures; lateral condyle fractures; medial epicondyle fractures; radial head and neck fractures; radial head subluxation.
Conclusion: Understanding of the ossification centres around the paediatric elbow is essential to correctly assessing and managing the common injuries that we have discussed in the review. Outcomes after these injuries are usually favourable with restoration of normal anatomy.

PMID: 29290878 [PubMed]

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KDM5B overexpression predicts a poor prognosis in patients with squamous cell carcinoma of the head and neck.

KDM5B overexpression predicts a poor prognosis in patients with squamous cell carcinoma of the head and neck.

J Cancer. 2018;9(1):198-204

Authors: Huang D, Qiu Y, Li G, Liu C, She L, Zhang D, Chen X, Zhu G, Zhang X, Tian Y, Liu Y

Abstract
Purpose: Lysine demethylase (KDM) 5B, as a member of the histone lysine demethylase family, is overexpressed and functions abnormally in various human cancers. However, its expression in the squamous cell carcinoma of the head and neck (SCCHN) remains unclear. Methods: KDM5B expression was analyzed by immunohistochemistry and correlated with clinicopathological parameters in 103 archival SCCHN tissue samples and 24 adjacent noncancerous epithelial tissues. Results: We found that KDM5B expression was higher in SCCHN than that in adjacent noncancerous tissues. This was closely associated with lymph node metastasis and tumor recurrence. In addition, Kaplan-Meier analysis revealed that patients with high KDM5B expression had shorter disease-free and overall survival times than those with low KDM5B expression. Importantly, both univariate and multivariate analysis demonstrated that KDM5B level was an independent prognostic factor in SCCHN patients. Conclusions: These results indicate that KDM5B is a valuable biomarker that can be used to predict SCCHN patient outcome.

PMID: 29290786 [PubMed]

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Outcome predictors in elderly head and neck free flap reconstruction: A retrospective study and systematic review of the current evidence.

Outcome predictors in elderly head and neck free flap reconstruction: A retrospective study and systematic review of the current evidence.

J Plast Reconstr Aesthet Surg. 2017 Dec 12;:

Authors: Goh CS, Kok YO, Yong CP, Tan EW, Goh LG, Chew KY, Teo CE, Goh TL

Abstract
Free flap tissue transfer has become the gold standard for reconstruction of composite head and neck defects. We sought to investigate the efficacy and morbidity of these procedures in the elderly. We retrospectively reviewed 245 head and neck free flap procedures (234 patients). Patients were stratified by age group (≥ or <65 years). Univariate and multivariate analyses were used to evaluate the following primary outcomes - free flap survival, postoperative medical and surgical complications and 30-day mortality. We found that free flap success and surgical complication rates were similar between the two age groups. Overall flap success and perioperative mortality rates were 94.3% and 2.1% respectively. Medical complications were significantly more common in the elderly group (p <0.001) and this correlated with comorbidity (OR = 2.81, p = 0.044) and advanced tumour stage (OR = 10.20, p= 0.029). Age was not independently associated with poor outcomes in our cohort. We then performed a systematic review of similar case-control studies worldwide and compared their findings with our results. We conclude that advanced age does not preclude free flap success in head and neck reconstruction. Rather, the presence of comorbidity appears to predict the development of medical complications postoperatively. Elderly patients with low comorbidity scores may be offered free flap reconstruction with less reservation.

PMID: 29290568 [PubMed - as supplied by publisher]

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Neural Entrainment to Speech Modulates Speech Intelligibility.

Neural Entrainment to Speech Modulates Speech Intelligibility.

Curr Biol. 2017 Dec 20;:

Authors: Riecke L, Formisano E, Sorger B, Başkent D, Gaudrain E

Abstract
Speech is crucial for communication in everyday life. Speech-brain entrainment, the alignment of neural activity to the slow temporal fluctuations (envelope) of acoustic speech input, is a ubiquitous element of current theories of speech processing. Associations between speech-brain entrainment and acoustic speech signal, listening task, and speech intelligibility have been observed repeatedly. However, a methodological bottleneck has prevented so far clarifying whether speech-brain entrainment contributes functionally to (i.e., causes) speech intelligibility or is merely an epiphenomenon of it. To address this long-standing issue, we experimentally manipulated speech-brain entrainment without concomitant acoustic and task-related variations, using a brain stimulation approach that enables modulating listeners' neural activity with transcranial currents carrying speech-envelope information. Results from two experiments involving a cocktail-party-like scenario and a listening situation devoid of aural speech-amplitude envelope input reveal consistent effects on listeners' speech-recognition performance, demonstrating a causal role of speech-brain entrainment in speech intelligibility. Our findings imply that speech-brain entrainment is critical for auditory speech comprehension and suggest that transcranial stimulation with speech-envelope-shaped currents can be utilized to modulate speech comprehension in impaired listening conditions.

PMID: 29290557 [PubMed - as supplied by publisher]

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Living in lower income zip codes is associated with more severe chronic rhinosinusitis.

Living in lower income zip codes is associated with more severe chronic rhinosinusitis.

Ann Allergy Asthma Immunol. 2017 Dec 28;:

Authors: Codispoti CD, Tapke DE, LoSavio PS, Batra PS, Mahdavinia M

PMID: 29290514 [PubMed - as supplied by publisher]

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[Sarcomatoid carcinoma of larynx. A histological challenge?]

[Sarcomatoid carcinoma of larynx. A histological challenge?]

Rev Esp Patol. 2018 Jan - Mar;51(1):30-33

Authors: Osorio-Velásquez A, Chiesa-Estomba CM, Betances-Reinoso FA, San Miguel-Fraile MP, Ortiz-Rey JA

Abstract
INTRODUCTION: Sarcomatoid carcinoma can occur in any part of the body; in the head and neck it occurs most frequently in the major salivary glands, with only about 1% of cases found in the larynx. As it has both epithelial and mesenchymal components, there are many theories concerning its origin and it can prove a diagnostic challenge.
CASE REPORT: A 76 year old male smoker presented with dysphonia. Vocal cord injury was found on examination but no lymphadenopathy or metastases were present. Laryngeal microsurgery was performed with complete excision of the lesion. Histopathology showed it to be a carcinosarcoma which showed intense and diffuse positivity for vimentin and focal positivity for AE1-AE3, CK5 and p63. The patient underwent radiotherapy as complementary treatment.
DISCUSSION: Sarcomatoid carcinoma usually presents with obstructive symptoms such as dysphonia. Prognosis depends on the stage and the presence or not of metastases. Both epithelial markers EMA, cytokeratin (AE1-AE3), epithelial membrane antigen, Ki 67 and mesenchymal markers such as vimentin, desmin, S-100 may be positive in these tumours. Recommended treatment for T2-T1 stages is an excisional biopsy which can be followed by adjuvant radiotherapy; radiotherapy alone has also been successful. T3-T4 stages can be treated with local excision, partial laryngectomy or total laryngectomy with subsequent ganglion emptying and concomitant radio and chemotherapy.

PMID: 29290320 [PubMed - in process]

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Comparison of transcanal endoscopic tympanoplasty with sterile acellular dermal allograft to conventional endaural microscopic tympanoplasty with tragal perichondrium.

Comparison of transcanal endoscopic tympanoplasty with sterile acellular dermal allograft to conventional endaural microscopic tympanoplasty with tragal perichondrium.

Am J Otolaryngol. 2017 Dec 07;:

Authors: Min J, Kim SH

Abstract
OBJECTIVES: This study aimed to compare the outcome of endoscopic tympanoplasty with sterile acellular dermal allograft (ADA) and conventional endaural microscopic tympanoplasty with tragal perichondrium.
METHODS: This was a retrospective comparative study of 53 patients (25 males and 28 females) with tympanic membrane perforation who underwent type I tympanoplasty in the department of otorhinolaryngology at a tertiary medical center from March 2011 to April 2017. The subjects were classified into two groups; transcanal endoscopic tympanoplasty with ADA (TET, n=26), conventional endaural microscopic tympanoplasty with autologous tragal perichondrium (EMT, n=27). Demographic data, perforation size of tympanic membrane at preoperative state, pure tone audiometric results preoperatively and 3months postoperatively, operation time, sequential postoperative pain scale, and postoperative graft failure rate were evaluated.
RESULTS: The perforation size of the tympanic membrane in TET and EMT group was 22.3±10.9% and 23.5±9.7%, respectively (P=0.143). Mean operation time of EMT (92.3±16.5min) was longer than that of the TET (65.3±20.5min) with a statistical significance (P=0.004). Graft success rate in the TET and EMT group were 92.3% and 96.3%, respectively; the values were not significantly different (P=0.610). Pre- and postoperative audiometric results including bone and air conduction thresholds and air-bone gap were not significantly different between the groups. In all groups, the postoperative air-bone gap was significantly improved compared to the preoperative air-bone gap. Pain in the immediate postoperative and day 1 after surgery were significantly less in the TET group.
CONCLUSION: With human cadaveric ADA, minimal invasive endoscopic tympanoplasty can be achieved with similar postoperative results and less pain.

PMID: 29290312 [PubMed - as supplied by publisher]

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Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis.

Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis.

Oral Oncol. 2018 Jan;76:52-60

Authors: Szturz P, Wouters K, Kiyota N, Tahara M, Prabhash K, Noronha V, Adelstein D, Vermorken JB

Abstract
OBJECTIVES: Altered fractionation radiotherapy and concomitant chemoradiotherapy represent commonly used intensification strategies in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This meta-analysis compares compliance, safety, and efficacy between two single-agent cisplatin schedules given concurrently with altered fractionation radiotherapy.
METHODS: We systematically searched for prospective trials of patients with LA-SCCHN who received post-operative or definitive altered fractionation concurrent chemoradiotherapy. High-dose cisplatin once every three to four weeks (100 mg/m2, 2 doses) was compared with a weekly low-dose protocol (≤50 mg/m2, ≥4 doses). The primary outcome was overall survival. The secondary endpoints comprised treatment adherence, acute and late toxicities, and objective response rate.
RESULTS: Twelve studies with 1373 patients treated with definitive chemoradiotherapy were included. Compared to the weekly low-dose cisplatin regimen, the three- to four-weekly high-dose cisplatin regimen improved overall survival (p=.0185), was more compliant with respect to receiving all planned cycles of cisplatin (71% versus 95%, p=.0353), and demonstrated less complications in terms of severe (grade 3-4) acute mucositis and/or stomatitis (75% versus 40%, p=.0202) and constipation (8% versus 1%, p=.0066), toxic deaths (4%, versus 1%, p=.0168), 30-day mortality (8% versus 3%, p=.0154), and severe late subcutaneous fibrosis (21% versus 2%, p<.0001). Overall and complete response rates were similar between both chemotherapy schedules.
CONCLUSION: In chemoradiotherapy incorporating altered fractionation, two cycles of high-dose cisplatin with a three to four week interval are superior to weekly low-dose schedules. Further studies should identify those who might derive the greatest benefit from this intensified approach.

PMID: 29290286 [PubMed - in process]

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Pre-Radiation dental considerations and management for head and neck cancer patients.

Pre-Radiation dental considerations and management for head and neck cancer patients.

Oral Oncol. 2018 Jan;76:42-51

Authors: Kufta K, Forman M, Swisher-McClure S, Sollecito TP, Panchal N

Abstract
Treatment of head and neck cancer (HNC) is accompanied by a high rate of morbidity, and complications can have a lifelong, profound impact on both patients and caregivers. Radiation-related injury to the hard and soft tissue of the head and neck can significantly decrease patients' quality of life. The purpose of this study is to provide patent-specific guidelines for managing the oral health and related side effects of HNC patients treated with radiation therapy. Based on reviewed articles retrieved on the PubMed database, guidelines for management of the oral health of this patient population were organized into three separate categories: cancer, patient, and dentition. The location, type, and staging of the cancer, along with the radiation used to treat the cancer significantly impact dental treatment. Several unique patient characteristics such as motivation, presence of support system, socioeconomic status, nutrition, and race have all been found to affect outcomes. Dental disease and available supportive dental management was found to significantly impact treatment and quality of life in this patient population. By comprehensively assessing unique cancer, patient, and dental-related factors, this review provides individualized evidence-based guidelines on the proper management of this complex and vulnerable patient population.

PMID: 29290285 [PubMed - in process]

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Oral cancer-derived exosomal NAP1 enhances cytotoxicity of natural killer cells via the IRF-3 pathway.

Oral cancer-derived exosomal NAP1 enhances cytotoxicity of natural killer cells via the IRF-3 pathway.

Oral Oncol. 2018 Jan;76:34-41

Authors: Wang Y, Qin X, Zhu X, Chen W, Zhang J, Chen W

Abstract
OBJECTIVE: To examine the effects of oral cancer-derived exosomes (OCEXs) on natural killer (NK) cells and to explore the underlying mechanism.
MATERIALS AND METHODS: OCEXs were isolated from the cell culture supernatant of oral cancer (OC) cells using ultrafiltration and affinity chromatography and were identified using electron microscopy, nanoparticle tracking analysis (NTA) and immunoblotting. The effects of OCEXs on NK cells were analyzed using laser scanning confocal microscopy and several functional assays of NK cells. To explore the mechanism of their effects, antibody array, protein mass spectrometry and RNA interference were adopted.
RESULTS: The particles isolated from the OC cells were identified as exosomes with satisfactory morphology, concentration and purity. The OCEXs were internalized by NK cells and then promoted the biological functions of NK cells, including proliferation, release of perforin and granzyme M and cytotoxicity. Furthermore, OCEXs increased the expression of interferon regulatory factor 3 (IRF-3) and its phosphorylation, which drove the expression of the type I interferon (IFN) gene and the chemokine (C-X-C motif) ligand (CXCL) genes, thereby promoting the functions of NK cells. In addition, NF-κB-activating kinase-associated protein 1 (NAP1), an upstream activator of IRF-3, was enriched in OCEXs, and treatment with OCEXs increased the expression of NAP1 in NK cells. Importantly, NAP1-depleted OCEXs obtained from OC cells had a dramatically weakened influence on NK cells.
CONCLUSION: Our findings reveal a previously unrecognized function of exosomal NAP1 derived from OC cells in enhancing the cytotoxicity of NK cells via the IRF-3 pathway.

PMID: 29290284 [PubMed - in process]

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Benzethonium chloride activates ER stress and reduces proliferation in HNSCC.

Benzethonium chloride activates ER stress and reduces proliferation in HNSCC.

Oral Oncol. 2018 Jan;76:27-33

Authors: Rayess HM, Xi Y, Garshott DM, Brownell AL, Yoo GH, Callaghan MU, Fribley AM

PMID: 29290283 [PubMed - in process]

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Optimising volumetric arc radiotherapy for dental rehabilitation in oropharynx cancer - A retrospective dosimetry review and feasibility planning study.

Optimising volumetric arc radiotherapy for dental rehabilitation in oropharynx cancer - A retrospective dosimetry review and feasibility planning study.

Oral Oncol. 2018 Jan;76:16-21

Authors: O'Cathail SM, Karir N, Shah K

Abstract
PURPOSE: To assess the dosimetry to dentally relevant substructures within the mandible/maxilla, establish the predictors of increased mean anterior mandible dose and assess the feasibility of rationale optimisation of dose to the anterior mandible (AM) volume to aid reconstructive dental surgery planning, where the AM is a critical structure.
MATERIALS AND METHODS: In a cohort of radically treated oropharynx cancer patients we conducted a retrospective dosimetry analysis of mandible/maxilla volumes, created using a published atlas. Comparisons of mean AM dose and clinical parameters between groups were tested using Wilcoxon rank-sum and Kruskal-Wallis tests. A multivariate linear regression model was created to assess independent predictors of increased mean AM dose. Patients with a mean AM dose over 37.5 Gy were included in feasibility planning study to test the hypothesis that it is possible to safely limit the dose whilst maintaining dose tolerances for other organs at risk.
RESULTS: 57 patients were included. Median AM mean dose was 32.2 Gy (IQR 27.7-38.7). T stage, N stage and inclusion of Level 1B were significantly associated with increased mean AM dose. Only T stage (p = .0132) and Level Ib inclusion (p = .018) remained significant in the linear regression model. 88% of plans, all of which included Level Ib, were successfully re-optimised without breaching accepted constraints.
CONCLUSIONS: Oropharynx cancer patients with advanced T stage and who require Level Ib treatment receive increased mean AM dose, potentially limiting surgical dental rehabilitation options. The majority of patients can be optimised safely with appropriate AM contouring.

PMID: 29290281 [PubMed - in process]

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Nanomedicine, an emerging therapeutic strategy for oral cancer therapy.

Nanomedicine, an emerging therapeutic strategy for oral cancer therapy.

Oral Oncol. 2018 Jan;76:1-7

Authors: Marcazzan S, Varoni EM, Blanco E, Lodi G, Ferrari M

Abstract
Oral cavity and oropharyngeal carcinomas (oral cancer) represents a significant cause of morbidity and mortality. Despite efforts in improving early diagnosis and treatment, the 5-year survival rate of advanced stage of the disease is less than 63%. The field of nanomedicine has offered promising diagnostic and therapeutic advances in cancer. Indeed, several platforms have been clinically approved for cancer therapy, while other promising systems are undergoing exploration in clinical trials. With its ability to deliver drugs, nucleic acids, and MRI contrast agents with high efficiency, nanomedicine platforms offer the potential to improve drug efficacy and tolerability. The aim of the present mini-review is to summarize the current preclinical status of nanotechnology systems for oral cancer therapy. The nanoplatforms for delivery of chemopreventive agents presented herein resulted in significantly higher anti-tumor activity than free forms of the drug, even against a chemo-resistant cell line. Impressive results have also been obtained using nanoparticles to deliver chemotherapeutics, resulting in reduced toxicity both in vitro and in vivo. Nanoparticles have also led to improvements in efficacy of photodynamic therapies through the development of targeted magnetic nanoparticles. Finally, gene therapy using nanoparticles demonstrated promising results specifically with regards to inhibition of gene expression. Of the few in vivo studies that have been reported, many of these used animal models with several limitations, which will be discussed herein. Lastly, we will discuss several future perspectives in oral cancer nanoparticle-based therapy and the development of appropriate animal models, distinguishing between oral cavity and oropharyngeal carcinoma.

PMID: 29290280 [PubMed - in process]

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Prevalence and trends of sensitisation to aeroallergens in patients with allergic rhinitis in Guangzhou, China: a 10-year retrospective study.

Prevalence and trends of sensitisation to aeroallergens in patients with allergic rhinitis in Guangzhou, China: a 10-year retrospective study.

BMJ Open. 2016 May 17;6(5):e011085

Authors: Wang W, Huang X, Chen Z, Zheng R, Chen Y, Zhang G, Yang Q

Abstract
OBJECTIVE: To investigate the prevalence and trends of sensitisation to common aeroallergens among outpatients with allergic rhinitis (AR) in Guangzhou, China, over the past decade.
DESIGN: A retrospective study; linear-by-linear association and simple linear regression were used to determine the trends in the prevalence of aeroallergen sensitisation.
SETTING: One grade-A hospital in Guangzhou, the largest city in southern China.
PARTICIPANTS: A total of 5486 patients (2297 males and 2489 females) who visited the ear, nose and throat outpatient clinic, from January 2005 to December 2014, were enrolled. All patients who presented with nasal hyper-reactive symptoms and who completed serological allergy testing, measuring specific IgE (sIgE) in the serum, were included. Among them, 4085 participants (2269 males and 1816 females) were diagnosed as being patients with AR.
OUTCOME MEASURES: Prevalence and trends of sensitisation to various types of aeroallergens were assessed.
RESULTS: The overall prevalence of sIgE-mediated sensitisation to aeroallergens in these patients with AR were as follows: 84.4% for house dust mites (HDMs), 23.4% for pet allergens, 21.1% for cockroaches, 9.1% for mould allergens, 7.7% for tree pollen and 6.0% for weed pollen. When all patients with nasal hyper-reactivity were stratified by decade of age, increasing age was associated with a decrease in sIgE positivity by ∼5.13% (95% CI -7.28% to -2.98%, p<0.01). Within the past decade, the prevalence of sensitisation to pet allergens in patients with AR increased at an annual rate of 1.3% (95% CI 0.85% to 1.67%, p<0.01).
CONCLUSIONS: This study demonstrated that HDMs comprised the most common aeroallergen in Guangzhou. The prevalence of sensitisation to aeroallergens decreased with increasing age. During the past decade, the prevalence of sensitisation to pet allergens showed an upward trend, suggesting an urgent need for its prevention and treatment.

PMID: 27188812 [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

PMID: 29291176 [PubMed]

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Effectiveness of adjuvant systemic chemotherapy for intermediate-risk stage IB cervical cancer.

Effectiveness of adjuvant systemic chemotherapy for intermediate-risk stage IB cervical cancer.

Oncotarget. 2017 Dec 05;8(63):106866-106875

Authors: Matsuo K, Shimada M, Yokota H, Satoh T, Katabuchi H, Kodama S, Sasaki H, Matsumura N, Mikami M, Sugiyama T

Abstract
Objective: To examine the effectiveness of systemic chemotherapy following radical hysterectomy for women with intermediate-risk stage IB cervical cancer.
Materials and Methods: This is a retrospective analysis of a previously organized nation-wide cohort study examining 6,003 women with stage IB-IIB cervical cancer who underwent radical hysterectomy between 2004 and 2008 in Japan. Survival of 555 women with stage IB cervical cancer in the intermediate-risk group (deep stromal invasion > 50%, large tumor size > 4 cm, and lympho-vascular space invasion [LVSI]) were examined based on adjuvant therapy patterns: chemotherapy alone (n = 223, 40.2%), concurrent chemo-radiotherapy (n = 172, 31.0%), and radiotherapy alone (n = 160, 28.8%).
Results: The most common intermediate-risk pattern was LVSI with deep stromal invasion (n = 216, 38.5%). The most common chemotherapeutic choice was taxane/platinum (52.2%). Women with adenocarcinoma/adenosquamous histology were more likely to receive chemotherapy (P = 0.03), and intermediate-risk pattern was not associated with chemotherapy use (P = 0.11). Women who received systemic chemotherapy had disease-free survival (5-year rate, 88.1% versus 90.2%, adjusted-hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.52-1.83, P = 0.94) and cause-specific survival (95.4% versus 94.8%, adjusted-HR 0.85, 95% CI 0.34-2.07, P = 0.71) similar to those who received concurrent chemo-radiotherapy on multivariable analysis. Similar results were seen among 329 women with multiple intermediate-risk factors (5-year rates for disease-free survival, chemotherapy versus concurrent chemo-radiotherapy, 87.1% versus 90.2%, P = 0.86; and cause-specific survival 94.6% versus 93.4%, P = 0.82). Cumulative local-recurrence (P = 0.77) and distant-recurrence (P = 0.94) risks were similar across the adjuvant therapy types.
Conclusions: Our study suggests that systemic chemotherapy may be an alternative treatment choice for adjuvant therapy in intermediate-risk stage IB cervical cancer.

PMID: 29290995 [PubMed]

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Emerging treatment options for ovarian cancer: focus on rucaparib.

Emerging treatment options for ovarian cancer: focus on rucaparib.

Int J Womens Health. 2017;9:913-924

Authors: Mariappan L, Jiang XY, Jackson J, Drew Y

Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting class of anticancer drugs, which have revolutionized the management of BRCA mutant/homologous recombination-deficient recurrent high-grade serous ovarian cancer (HGSOC). With three PARPi now approved by the US Food and Drug Administration, olaparib (Lynparza™), niraparib (Zejula™), and rucaparib (Rubraca™) in 2014 (and 2017 for the tablet formulation), 2016, and 2017, respectively, these drugs have now entered routine clinical practice. The marked single-agent efficacy of PARPi either as maintenance following response to platinum-based chemotherapy or as up-front treatment in these indications is based on the well-known concept of synthetic lethality. PARPi themselves work by blocking the repair of single-strand DNA breaks by the base excision/single-strand break repair pathway and can also be directly cytotoxic by the mechanism of PARP trapping. The greatest benefit in terms of progression-free survival, in all three PARPi maintenance registration studies, was seen in women with platinum-sensitive BRCA mutation-associated HGSOC. However, it is clear that non-BRCA HGSOC can benefit from PARPi and the ongoing challenge of biomarker driven studies is how best to define these patients. PARPi are well tolerated, but more information is needed to assess the longer-term/later onset toxicities as these agents are investigated in the first-line setting. The future direction and challenges for PARPi will be to continue to expand beyond BRCA and ovarian cancer by identifying molecular or functional signatures of response; to see if the durable responses in ovarian cancer can be improved and efficacy can be achieved in other cancer sub-types by combining with novel targeted agents. This review summarizes the development of PARPi as a class in ovarian cancer with particular focus on the PARPi rucaparib.

PMID: 29290694 [PubMed]

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[Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].

[Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].

Bull Cancer. 2017 Dec 28;:

Authors: Bernard-Tessier A, Bonnet C, Lavaud P, Gizzi M, Loriot Y, Massard C

Abstract
Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq®) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing.

PMID: 29290331 [PubMed - as supplied by publisher]

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Risk factors for local recurrence after lobectomy and lymph node dissection in patients with non-small cell lung cancer: Implications for adjuvant therapy.

Risk factors for local recurrence after lobectomy and lymph node dissection in patients with non-small cell lung cancer: Implications for adjuvant therapy.

Lung Cancer. 2018 Jan;115:28-33

Authors: Isaka M, Kojima H, Takahashi S, Omae K, Ohde Y

Abstract
OBJECTIVES: The objective of this study was to investigate clinicopathological risk factors for local recurrence in patients who underwent either complete resection with lobectomy or more extensive resection with hilar and mediastinal lymph node dissection for non-small cell lung cancer (NSCLC). The role of adjuvant therapy was also explored.
MATERIALS AND METHODS: We reviewed the records of 1012 consecutive stage I-III NSCLC patients who underwent complete resection. The median follow-up time was 59 months. The risk factors for local recurrence were investigated by multivariate analysis using Cox's proportional hazards regression model.
RESULTS: Local recurrence was identified in 9.4% of the patients. The most significant risk factor for local recurrence was lymph node metastasis (N1: hazard ratio [HR]=2.27, p=0.009; N2: HR=6.85, p<0.0001). For the subgroup of patients with lymph node metastasis (n=289), the independent risk factors for local recurrence were N2 disease with N1 metastasis (N2 with N1; HR=3.46, p<0.0001) and non-receipt of adjuvant platinum-based chemotherapy (HR=1.91, p=0.018). The 5-year freedom from local recurrence rates were 96.1%, 84.1%, 85.0%, and 53.5% for N0, N1, skip N2, and N2 with N1 stages (p<0.0001).
CONCLUSION: Local recurrence is significantly associated with poor overall survival. Therefore, local control is essential for radical cure of NSCLC. N2 with N1 status was the primary risk factor for local recurrence, while adjuvant chemotherapy improved local control. These data have important implications for postoperative radiotherapy and highlight the need to devise more effective eligibility criteria for this modality in patients with lymph node metastasis.

PMID: 29290258 [PubMed - in process]

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Dynamic change of fatigue of pemetrexed maintenance treatment in the JMEN trial.

Dynamic change of fatigue of pemetrexed maintenance treatment in the JMEN trial.

Lung Cancer. 2018 Jan;115:121-126

Authors: Zhang L, Belani CP, Zhang PH, Wang X, Yang L, Orlando M, Wu YL

Abstract
OBJECTIVES: In the JMEN trial, patients with advanced non-squamous non-small cell lung cancer (NSCLC) without progression after platinum-based first-line therapy derived extended survival, delayed disease progression, and maintained overall quality of life (QoL) from pemetrexed maintenance therapy. However, fatigue was the most common physician-reported non-hematological toxicity in the pemetrexed group. This post hoc analysis investigated dynamic change of fatigue.
MATERIALS AND METHODS: Analysis of the overall safety population with squamous and non-squamous NSCLC subgroups included Common Terminology Criteria for Adverse Events to summarize adverse event (AE) rates by cycle and AE investigator-reported severity. Worsening of fatigue, defined as +15mm or more from baseline on a 100mm scale, evaluated QoL using the patient-reported Lung Cancer Symptom Scale. Patients with worsening fatigue and time-to-worsening of fatigue symptoms were also analyzed.
RESULTS: Drug-related fatigue occurred more frequently with pemetrexed than placebo. The drug-related grade 3/4 fatigue was also higher in the overall population on pemetrexed than with placebo. Fatigue incidence during pemetrexed maintenance after induction was not altered with cumulative exposure. Percentage of patients who experienced worsening of fatigue based on patient-reported LCSS scores was comparable between the two arms in cycles 1-10. The time-to-worsening of fatigue was similar between the pemetrexed arm and the placebo arm in the overall population; however, the East Asian subpopulation patients taking pemetrexed experienced a longer median time-to-worsening of fatigue than patients taking placebo.
CONCLUSION: Analyses suggest that despite higher incidence of any grade drug-related fatigue compared with placebo in patients with advanced NSCLC, pemetrexed maintenance does not impair patient-reported QoL.

PMID: 29290253 [PubMed - in process]

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A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404.

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404.

Lung Cancer. 2018 Jan;115:103-108

Authors: Ninomiya T, Nogami N, Kozuki T, Harada D, Kubo T, Ohashi K, Kuyama S, Kudo K, Bessho A, Fukamatsu N, Fujimoto N, Aoe K, Shibayama T, Sugimoto K, Takigawa N, Hotta K, Kiura K

Abstract
OBJECTIVE: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis.
MATERIALS AND METHODS: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose.
RESULTS: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease.
CONCLUSION: Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

PMID: 29290249 [PubMed - in process]

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Nanozymes Decorated Metal-Organic Frameworks for Enhanced Photodynamic Therapy.

Nanozymes Decorated Metal-Organic Frameworks for Enhanced Photodynamic Therapy.

ACS Nano. 2017 Dec 31;:

Authors: Zhang Y, Wang F, Liu C, Wang Z, Kang L, Huang Y, Dong K, Ren J, Qu X

Abstract
Metal-organic frameworks (MOFs) have been used for photodynamic therapy (PDT) of cancers by integrating photosensitizers, which cause cytotoxic effects on cancer cells by converting tumor oxygen into reactive singlet oxygen (1O2). However, the PDT efficiency of MOFs is severely limited by tumor hypoxia. Herein, by decorating platinum nanozymes on photosensitizers integrated MOFs, we report a simple yet versatile strategy for enhanced photodynamic therapy. The platinum nanoparticles homogeneously immobilized on MOFs possess high stability and catalase-like activity. Thus, our nanoplatform can facilitate the formation of 1O2 in hypoxic tumor site via H2O2-activated evolvement of O2, which can cause more serious damage to cancer cells. Our finding highlights the composites of nanozymes and MOFs have the potential to serve as efficient agents for cancer therapy, which will open an avenue of nanozymes and MOFs toward biological applications.

PMID: 29290107 [PubMed - as supplied by publisher]

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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.

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.

http:--arjournals.annualreviews.org-imag

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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