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https://www.readbyqxmd.com/read/29328464/inhibition-of-gli-leads-to-antitumor-growth-and-enhancement-of-cisplatin-induced-cytotoxicity-in-large-cell-neuroendocrine-carcinoma-of-the-lung
#1
Tsukasa Ishiwata, Shunichiro Iwasawa, Takahiro Ebata, Mengmeng Fan, Yuji Tada, Koichiro Tatsumi, Yuichi Takiguchi
Large cell neuroendocrine carcinoma (LCNEC) of the lung is a highly aggressive tumor without established standard treatment. The Hedgehog (Hh) signal, which is critical in embryogenesis, is known to play important roles in maintaining a malignant phenotype in various cancers. The present study explored the possibility of targeting the Hh signal in the treatment of LCNEC by suppressing Hh downstream molecules, Smoothened (Smo) and GLI family zinc finger 1/2 (Gli1/2), in 3 human LCNEC cell lines. Smo inhibitor, BMS-833923, and Gli inhibitor, GANT61, downregulated Gli1 and 2, resulting in the suppression of the cell viability of the 3 cell lines as assessed using an MTT assay...
January 3, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29326074/overcoming-the-resistance-mechanisms-of-smoothened-inhibitors
#2
REVIEW
Xiaochun Dong, Chenglin Wang, Zhongjian Chen, Weili Zhao
Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors...
January 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29320962/replantation-and-revascularization-of-amputated-upper-limb-appendages-outcome-and-predicting-the-factors-influencing-the-success-rates-of-these-procedures-in-a-tertiary-hospital-an-8-year-retrospective-cross-sectional-study
#3
Tunku Kamarul, Azura Mansor, Noorzurani Robson, Salim Hh Albusaidi, Abdulrazzaq M Suhaeb, Ely Z Samsudin
PURPOSE: Worldwide advances in microsurgery have made salvaging of amputated hand via replantation and revascularization common procedures. The present study examines the outcome of these procedures in a tertiary hospital in Malaysia. METHODS: Patients with hand amputation who underwent replantation or revascularization from 2005 to 2012 were identified and reviewed for patient characteristics, amputation characteristics and survival rates. Successfully treated patients were interviewed to assess the functional outcome using Quick Disability of the Arm, Shoulder and Hand (Quick-DASH) questionnaire and Michigan Hand Outcome Questionnaire (MHQ)...
January 2018: Journal of Orthopaedic Surgery
https://www.readbyqxmd.com/read/29319456/comt-genotype-and-sensory-and-sensorimotor-gating-in-high-and-low-hypnotizable-subjects
#4
Zinaida I Storozheva, Anna V Kirenskaya, Mikhail N Gordeev, Maria E Kovaleva, Vladimir Yu Novototsky-Vlasov
We investigated the association between hypnotizability, COMT polymorphism, P50 suppression ratio, and prepulse inhibition of acoustic startle response (ASR) in 21 high (HH) and 19 low (LH) hypnotizable subjects. The frequency of Met/Met carriers of COMT polymorphysm was higher in HH than in LH group (33.3% versus 10.6%, p = .049). Increased ASR amplitude and latency and decreased prepulse inhibition at 120 ms lead interval were found in the HH compared to the LH group. The effect of COMT genotype on prepulse inhibition was observed in LH group only...
January 2018: International Journal of Clinical and Experimental Hypnosis
https://www.readbyqxmd.com/read/29318655/design-of-nonapeptide-lvffarkhh-a-bifunctional-agent-against-cu2-mediated-amyloid-%C3%AE-protein-aggregation-and-cytotoxicity
#5
Huan Zhang, Chong Zhang, Xiao-Yan Dong, Jie Zheng, Yan Sun
Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu2+ exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu2+ -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu2+ with a dissociation constant of 5...
January 10, 2018: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/29316328/anti-fibrotic-effects-of-pirfenidone-by-interference-with-the-hedgehog-signalling-pathway-in-patients-with-systemic-sclerosis-associated-interstitial-lung-disease
#6
Hua Xiao, Guang-Feng Zhang, Xiang-Ping Liao, Xiao-Jie Li, Jian Zhang, Haobo Lin, Zhe Chen, Xiao Zhang
AIM: To determine whether pirfenidone attenuates lung fibrosis by interfering with the hedgehog (Hh) signalling pathway in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Twenty-five SSc-ILD patients (20 first visit, five who underwent pirfenidone treatment for 6 months) and 10 healthy controls were recruited. Lung tissues were obtained by open-chest surgery, and primary lung fibroblasts were isolated, cultured and stimulated with pirfenidone...
January 7, 2018: International Journal of Rheumatic Diseases
https://www.readbyqxmd.com/read/29315702/strategies-to-target-the-hedgehog-signaling-pathway-for-cancer-therapy
#7
REVIEW
Minhang Xin, Xinyue Ji, Ladie Kimberly De La Cruz, Suresh Thareja, Binghe Wang
Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma...
January 5, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29311408/hepatic-hydrothorax
#8
Yong Lv, Guohong Han, Daiming Fan
Hepatic hydrothorax (HH) is a pleural effusion that develops in a patient with cirrhosis and portal hypertension in the absence of cardiopulmonary disease. Although the development of HH remains incompletely understood, the most acceptable explanation is that the pleural effusion is a result of a direct passage of ascitic fluid into the pleural cavity through a defect in the diaphragm due to the raised abdominal pressure and the negative pressure within the pleural space. Patients with HH can be asymptomatic or present with pulmonary symptoms such as shortness of breath, cough, hypoxemia, or respiratory failure associated with large pleural effusions...
December 27, 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/29310877/effects-of-different-peracetic-acid-formulations-on-post-space-radicular-dentin
#9
Lauriê Garcia Belizário, Milton Carlos Kuga, Gabriela Mariana Castro-Núñez, Wilfredo Gustavo Escalante-Otárola, Marcus Vinicius Reis Só, Jefferson Ricardo Pereira
STATEMENT OF PROBLEM: The optimal irrigating solution with antimicrobial and dentin cleansing properties for post space preparation for fiber posts is unclear. Peracetic acid is one option but is available in various chemical formulations that require evaluation. PURPOSE: The purpose of this in vitro study was to evaluate dentin surface cleanliness based on the presence of a smear layer and the number of open dentin tubules. It also investigates the chemical composition of residues after canal irrigation with a 1% peracetic acid solution (PA) at low or high concentration of hydrogen peroxide during the preparation of intracanal fiber posts...
January 5, 2018: Journal of Prosthetic Dentistry
https://www.readbyqxmd.com/read/29305793/coadministration-of-polymeric-conjugates-of-docetaxel-and-cyclopamine-synergistically-inhibits-orthotopic-pancreatic-cancer-growth-and-metastasis
#10
Saud A Almawash, Goutam Mondal, Ram I Mahato
PURPOSE: The aim of this study was to determine whether co-administration of hedgehog (Hh) pathway inhibitor cyclopamine (CYP) and microtubule stabilizer docetaxel (DTX) as polymer-drug conjugates, methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cyclopamine) (P-CYP) and methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-docetaxel) (P-DTX) could synergistically inhibit orthotopic pancreatic tumor growth in NSG mice...
January 5, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29302131/climate-smart-agriculture-farm-household-typologies-and-food-security-an-ex-ante-assessment-from-eastern-india
#11
Santiago Lopez-Ridaura, Romain Frelat, Mark T van Wijk, Diego Valbuena, Timothy J Krupnik, M L Jat
One of the great challenges in agricultural development and sustainable intensification is the assurance of social equity in food security oriented interventions. Development practitioners, researchers, and policy makers alike could benefit from prior insight into what interventions or environmental shocks might differentially affect farmers' food security status, in order to move towards more informed and equitable development. We examined the food security status and livelihood activities of 269 smallholder farm households (HHs) in Bihar, India...
January 2018: Agricultural Systems
https://www.readbyqxmd.com/read/29301508/quality-of-life-scores-differs-between-genotypic-groups-of-patients-with-suspected-hereditary-hemochromatosis
#12
Paula Fernanda Silva Fonseca, Rodolfo Delfini Cançado, Flavio Augusto Naoum, Carla Luana Dinardo, Guilherme Henrique Hencklain Fonseca, Sandra Fatima Menosi Gualandro, José Eduardo Krieger, Alexandre Costa Pereira, Pierre Brissot, Paulo Caleb Junior Lima Santos
BACKGROUND: Hereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient's quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload...
January 5, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29301237/synthesis-and-smo-activity-of-some-novel-benzamide-derivatives
#13
Huaiwei Ding, Kai Chen, Bingke Song, Chenglong Deng, Wei Li, Li Niu, Mengxuan Bai, Hongrui Song, Lijuan Zhang
Two series of benzamides compounds bearing piperidine groups were synthesized and the Gli-luc luciferase activity was screened by Gys-luc luciferase gene detection method. Compound 5q showed promising inhibition of hedgehog (Hh) signaling pathway. To further verify whether the Hh inhibitory activities of the target compounds are derived from their inhibition to the Smoothened (Smo) receptor, the compounds with good potency were evaluated in a fluorescence competitive displacement assays, the results showed the Smo inhibitory potency of these compounds correlated well with their Hh inhibition, which suggested that the observed Hh activity was driven by Smo inhibitors...
December 31, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29300865/crispr-cas9-mediated-tspo-gene-mutations-lead-to-reduced-mitochondrial-membrane-potential-and-steroid-formation-in-ma-10-mouse-tumor-leydig-cells
#14
Jinjiang Fan, Kevin Wang, Barry Zirkin, Vassilios Papadopoulos
The outer mitochondrial membrane translocator protein (TSPO) binds cholesterol with high affinity and is involved in mediating its delivery into mitochondria, the rate-limiting step in hormone-induced steroidogenesis. Specific ligand binding to TSPO has been shown to initiate steroid formation. However, recent studies of the genetic deletion of Tspo have provided conflicting results. Here we address and extend previous studies by examining the effects of Tspo - specific mutations on steroid formation in the hormone- and cAMP-responsive MA-10 cells, using the CRISPR/Cas9 system...
December 28, 2017: Endocrinology
https://www.readbyqxmd.com/read/29300747/household-expenditure-on-leprosy-outpatient-services-in-the-indian-health-system-a-comparative-study
#15
Anuj Tiwari, Pramilesh Suryawanshi, Akash Raikwar, Mohammad Arif, Jan Hendrik Richardus
BACKGROUND: Leprosy is a major public health problem in many low and middle income countries, especially in India, and contributes considerably to the global burden of the disease. Leprosy and poverty are closely associated, and therefore the economic burden of leprosy is a concern. However, evidence on patient's expenditure is scarce. In this study, we estimate the expenditure in primary care (outpatient) by leprosy households in two different public health settings. METHODOLOGY / PRINCIPAL FINDINGS: We performed a cross-sectional study, comparing the Union Territory of Dadra and Nagar Haveli with the Umbergaon block of Valsad, Gujrat, India...
January 4, 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29290584/crispr-screens-uncover-genes-that-regulate-target-cell-sensitivity-to-the-morphogen-sonic-hedgehog
#16
Ganesh V Pusapati, Jennifer H Kong, Bhaven B Patel, Arunkumar Krishnan, Andreas Sagner, Maia Kinnebrew, James Briscoe, L Aravind, Rajat Rohatgi
To uncover regulatory mechanisms in Hedgehog (Hh) signaling, we conducted genome-wide screens to identify positive and negative pathway components and validated top hits using multiple signaling and differentiation assays in two different cell types. Most positive regulators identified in our screens, including Rab34, Pdcl, and Tubd1, were involved in ciliary functions, confirming the central role for primary cilia in Hh signaling. Negative regulators identified included Megf8, Mgrn1, and an unannotated gene encoding a tetraspanin protein we named Atthog...
December 26, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29286036/-perforated-chronic-gastric-ulcer-in-sliding-hiatus-hernia
#17
S G Gorin, V I Khrupkin, A E Kustov, B A Andronov, A A Stradymov, A A Pisarevskaya, A M Verenok, V D Lyutov
No abstract text is available yet for this article.
2017: Khirurgiia
https://www.readbyqxmd.com/read/29280746/congenital-hyperinsulinism-diagnosis-and-treatment-update
#18
Hüseyin Demirbilek, Khalid Hussain
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate seretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH...
December 27, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/29279097/epigenetic-regulation-of-the-hedgehog-and-wnt-pathways-in-cancer
#19
REVIEW
Leon J Wils, Maarten F Bijlsma
The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway regulators contributes to the genesis and progression of several cancer types. In addition, the impact of epigenetic regulation of the Hh and Wnt pathways on cancer is becoming increasingly clear. In this review, current knowledge on the epigenetic control of Hh and Wnt and the impact on tumor formation will be discussed...
January 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29278695/carcinogenicity-assessment-of-the-hedgehog-pathway-inhibitor-vismodegib-in-tg-rash2-mice-and-sprague-dawley-rats
#20
Jinze Li, Eric Morinello, Thomas Larsen, Denzil Frost, Ivor Caro, Stephen Gould, Lisa Wong, Angela Hendricks, Noel Dybdal, Donna Dambach, Melissa Schutten
Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0...
December 23, 2017: Regulatory Toxicology and Pharmacology: RTP
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