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https://www.readbyqxmd.com/read/28318251/molecular-simulation-studies-on-the-binding-selectivity-of-type-i-inhibitors-in-the-complexes-with-ros1-versus-alk
#1
Yuanxin Tian, Yonghuan Yu, Yudong Shen, Hua Wan, Shan Chang, Tingting Zhang, Shanhe Wan, Jiajie Zhang
ROS1 and ALK are promising targets of anti-cancer drugs for non small cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, selective ROS1 inhibitor is relative rarely. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28316074/a-comparison-of-alk-gene-rearrangement-and-alk-protein-expression-in-primary-lung-carcinoma-and-matched-metastasis
#2
Humberto E Trejo Bittar, Alyssa Luvison, Caitlyn Miller, Sanja Dacic
AIMS: The 2013 CAP/IASLC/AMP guideline for EGFR and ALK testing in lung carcinoma indicates that either the primary tumor or the metastasis is suitable for testing. The heterogeneity of gene mutations has been extensively studied, while similar reports on gene rearrangements are limited. The aim of this study was to determine if ALK status between primary tumor and matched metastasis differs. METHODS AND RESULTS: 15 ALK-FISH rearranged and 19 non-ALK-FISH rearranged adenocarcinomas were retrospectively collected based on availability of tissue from a matched metastatic site...
March 17, 2017: Histopathology
https://www.readbyqxmd.com/read/28315448/scaffold-hopping-identifies-6-8-disubstituted-purines-as-novel-anaplastic-lymphoma-kinase-inhibitors
#3
Laura Schlütke, Markus Immer, Lutz Preu, Frank Totzke, Christoph Schächtele, Michael H G Kubbutat, Conrad Kunick
Rearrangements of anaplastic lymphoma kinase (ALK) are associated with several cancer diseases. Due to resistance development against existing ALK-inhibitors, new, structurally unrelated inhibitors are required. By a scaffold hopping strategy, 6,8-disubstituted purines were designed as analogues of similar ALK-inhibiting thieno[3,2-d]pyrimidines. While the new title compounds indeed inhibited ALK and several ALK mutants in submicromolar concentrations, they retained poor water solubility.
March 14, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28314727/transcriptomic-analyses-elucidate-adaptive-differences-of-closely-related-strains-of-p-aeruginosa-in-fuel
#4
Thusitha S Gunasekera, Loryn L Bowen, Carol E Zhou, Susan C Howard-Byerly, William S Foley, Richard C Striebich, Larry C Dugan, Oscar N Ruiz
Pseudomonas aeruginosa can utilize hydrocarbons, but different strains have varying degrees of adaptation despite their highly conserved genome. P. aeruginosa ATCC 33988 is highly adapted to hydrocarbons while strain PAO1, a human pathogen, is less-adapted and degrades jet fuel at a slower rate than does ATCC 33988. We investigated fuel specific transcriptomic differences between these strains in order to ascertain the underling mechanisms utilized by the adapted strain to proliferate in fuel. During growth in fuel, the genes related to alkane degradation, heat-shock response, membrane proteins, efflux pumps and several novel genes were upregulated in ATCC 33988...
March 17, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28303028/alectinib-ch5424802-antagonizes-abcb1-and-abcg2-mediated-multidrug-resistance-in-vitro-in-vivo-and-ex-vivo
#5
Ke Yang, Yifan Chen, Kenneth Kin Wah To, Fang Wang, Delan Li, Likun Chen, Liwu Fu
Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo...
March 17, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28302170/identification-of-residues-important-for-the-activity-of-aldehyde-deformylating-oxygenase-through-investigation-into-the-structure-activity-relationship
#6
Qing Wang, Luyao Bao, Chenjun Jia, Mei Li, Jian-Jun Li, Xuefeng Lu
BACKGROUND: Aldehyde-deformylating oxygenase (ADO) is a key enzyme involved in the biosynthetic pathway of fatty alk(a/e)nes in cyanobacteria. However, cADO (cyanobacterial ADO) showed extreme low activity with the k cat value below 1 min(-1), which would limit its application in biofuel production. To identify the activity related key residues of cADO is urgently required. RESULTS: The amino acid residues which might affect cADO activity were identified based on the crystal structures and sequence alignment of cADOs, including the residues close to the di-iron center (Tyr39, Arg62, Gln110, Tyr122, Asp143 of cADO-1593), the protein surface (Trp 178 of cADO-1593), and those involved in two important hydrogen bonds (Gln49, Asn123 of cADO-1593, and Asp49, Asn123 of cADO-sll0208) and in the oligopeptide whose conformation changed in the absence of the di-iron center (Leu146, Asn149, Phe150 of cADO-1593, and Thr146, Leu148, Tyr150 of cADO-sll0208)...
March 16, 2017: BMC Biotechnology
https://www.readbyqxmd.com/read/28299304/effects-of-phlebotomy-on-liver-enzymes-and-histology-of-patients-with-nonalcoholic-fatty-liver-disease
#7
Mahsa Khodadoostan, Maryam Zamanidoost, Ahmad Shavakhi, Hosein Sanei, Masood Shahbazi, Mehdi Ahmadian
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), defined as excessive liver fat deposition and one of end-stage liver disease causes. Increased ferritin levels are associated with insulin resistance and a higher hepatic iron and fat content. Hyperferritinemia has been associated with severity of liver damage in NAFLD. The study aimed to evaluate the effects of phlebotomy on liver enzymes and histology in such patients. MATERIALS AND METHODS: Thirty-two eligible patients who had NAFLD and after 6 months of lifestyle modification still had NAFLD, and whose ferritin serum was above 250 mg/dl, were enrolled in this clinical trial study...
2017: Advanced Biomedical Research
https://www.readbyqxmd.com/read/28296581/three-year-follow-up-of-an-alectinib-phase-i-ii-study-in-alk-positive-non-small-cell-lung-cancer-af-001jp
#8
Tomohide Tamura, Katsuyuki Kiura, Takashi Seto, Kazuhiko Nakagawa, Makoto Maemondo, Akira Inoue, Toyoaki Hida, Hiroshige Yoshioka, Masao Harada, Yuichiro Ohe, Naoyuki Nogami, Haruyasu Murakami, Hiroshi Kuriki, Tadashi Shimada, Tomohiro Tanaka, Kengo Takeuchi, Makoto Nishio
Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy...
March 15, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28293988/molecular-profiling-of-papillary-thyroid-carcinoma-in-korea-with-high-prevalence-of-braf-v600e-mutation
#9
Seung Eun Lee, Tae Sook Hwang, Yoon-La Choi, Wook Youn Kim, So Duk Lim, Young Bum Yoo, Suk Kyeong Kim
BACKGROUND: BRAF V600E mutation in PTC is particularly prevalent in Korea and a considerable number of BRAF-wild PTCs harbor RAS mutations. In addition, subsets of other genetic alterations clearly exist, but their prevalence in the Korean population has not been well studied. Recent increased insight into noninvasive encapsulated follicular variant PTC (NIE-FVPTC) has prompted endocrine pathologists to reclassify this entity as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features...
March 15, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28293986/clear-cell-change-in-thyroid-carcinoma-a-clinicopathologic-and-molecular-study-with-identification-of-variable-genetic-anomalies
#10
Nicole A Cipriani, Shweta Agarwal, Dora Dias-Santagata, William C Faquin, Peter M Sadow
Clear cell carcinoma of the thyroid has been regarded as a variant of follicular (FTC) or papillary (PTC) thyroid carcinoma. 21 primary thyroid carcinomas with clear cell features, diagnosed in 20 patients (12 female, 8 male) were identified between 1992 and 2012 (0.5% of in-house thyroid carcinomas). H&E slides were reviewed. SNaPshot multi-gene mutational analysis and a translocation panel were successfully performed on 15 of these cases. 12 (57%) were FTC, 5 were conventional PTC, 2 were follicular variant (FV) of PTC, and 2 were poorly differentiated thyroid carcinoma (PDTC)...
March 15, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28292932/crystal-structure-of-the-human-alkaline-sphingomyelinase-provides-insights-into-substrate-recognition
#11
Alexei Gorelik, Fangyu Liu, Katalin Illes, Bhushan Nagar
Absorption of dietary sphingomyelin (SM) requires its initial degradation into ceramide, a process catalyzed by the intestinal enzyme alkaline sphingomyelinase (alk-SMase, NPP7, ENPP7). Alk-SMase belongs to the nucleotide pyrophosphatase / phosphodiesterase family, the members of which hydrolyze nucleoside phosphates, phospholipids and other related molecules. NPP7 is the only paralog that can cleave SM, and its activity requires the presence of bile salts, a class of physiological anionic detergents. To elucidate the mechanism of substrate recognition, we determined the crystal structure of human alk-SMase in complex with phosphocholine, a reaction product...
March 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28290719/molecular-dynamics-and-pharmacophore-modelling-studies-of-different-subtype-alk-and-egfr-t790m-inhibitors-in-nsclc
#12
P K Singh, O Silakari
Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r(2) = 0.96, q(2) = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r(2) = 0.92, q(2) = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M)...
March 14, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28285695/optimal-management-of-alk-positive-nsclc-progressing-on-crizotinib
#13
REVIEW
Giulio Metro, Marco Tazza, Roberta Matocci, Rita Chiari, Lucio Crinò
Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285694/sbrt-for-oligoprogressive-oncogene-addicted-nsclc
#14
REVIEW
L Basler, S G C Kroeze, M Guckenberger
Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285691/renal-cyst-formation-in-patients-treated-with-crizotinib-for-non-small-cell-lung-cancer-incidence-radiological-features-and-clinical-characteristics
#15
Darragh F Halpenny, Sinead McEvoy, Angela Li, Sumar Hayan, Marinela Capanu, Junting Zheng, Gregory Riely, Michelle S Ginsberg
Treatment with the ALK inhibitor crizotinib has been associated with complex renal cyst formation in patients with non-small cell lung cancer (NSCLC). Using patients treated with crizotinib, we aimed to evaluate the incidence of renal cyst formation, to identify risk factors for cyst formation and to provide a radiological description of cyst characteristics. Patients with ALK-positive NSCLC treated with crizotinib were retrospectively identified from an institutional database. Computed tomography (CT) imaging performed prior to and during crizotinib treatment was retrospectively reviewed to assess the size and complexity of pre-existing cysts, new cysts, and enlarging cysts...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285687/met-exon-14-skipping-mutation-in-triple-negative-pulmonary-adenocarcinomas-and-pleomorphic-carcinomas-an-analysis-of-intratumoral-met-status-heterogeneity-and-clinicopathological-characteristics
#16
Dohee Kwon, Jaemoon Koh, Sehui Kim, Heounjeong Go, Young A Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Yoon Kyung Jeon, Doo Hyun Chung
OBJECTIVES: MET mutations leading to exon 14 skipping rarely occur in non-small cell lung cancer (NSCLC). Recently, small molecule inhibitors targeting MET mutations showed clinical benefit. However, the clinicopathological characteristics of NSCLC harboring MET mutations, and the correlation among mutations, protein expression, and gene copy number of MET in NSCLC remain unclear. Therefore, we address these issues. MATERIALS AND METHODS: MET exon 14 skipping mutations were evaluated using real-time quantitative reverse-transcription-PCR (qRT-PCR) in 102 triple-negative (i...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285684/dual-occurrence-of-alk-g1202r-solvent-front-mutation-and-small-cell-lung-cancer-transformation-as-resistance-mechanisms-to-second-generation-alk-inhibitors-without-prior-exposure-to-crizotinib-pitfall-of-solely-relying-on-liquid-re-biopsy
#17
Sai-Hong Ignatius Ou, Thomas K Lee, Lauren Young, Maria Y Fernandez-Rocha, Dean Pavlick, Alexa B Schrock, Viola W Zhu, Jeffrey Milliken, Siraj M Ali, Barbara J Gitlitz
Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285324/novel-therapeutics-for-stargardt-disease
#18
REVIEW
Louise J Lu, Ji Liu, Ron A Adelman
DESCRIPTION OF SITUATION: Stargardt disease, an inherited macular dystrophy caused by mutations in the ABCA4 gene encoding a retinal transporter protein, is the most prevalent form of macular degeneration in children. Patients with Stargardt disease develop severe vision loss within their first or second decades of life, which progresses to irreversible decreased visual acuity in almost all cases. Presently, there are no standard treatments for Stargardt disease. However, encouraging progress has been made in the development of innovative approaches to preventing vision loss in Stargardt patients...
March 11, 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28280984/treatment-of-lung-adenocarcinoma-by-molecular-targeted-therapy-and-immunotherapy
#19
REVIEW
Motonobu Saito, Hiroyuki Suzuki, Koji Kono, Seiichi Takenoshita, Takashi Kohno
Lung adenocarcinoma (LADC) is a cancer treatable using targeted therapies against driver gene aberrations. EGFR mutations and ALK fusions are frequent gene aberrations in LADC, and personalized therapies against those aberrations have become a standard therapy. These targeted therapies have shown significant positive efficacy and tolerable toxicity compared to conventional chemotherapy, so it is necessary to identify additional druggable genetic aberrations. Other than EGFR mutations and ALK fusions, mutations in KRAS, HER2, and BRAF, and driver fusions involving RET and ROS1, have also been identified in LADC...
March 9, 2017: Surgery Today
https://www.readbyqxmd.com/read/28280611/baseline-hemoglobin-and-liver-function-predict-tolerability-and-overall-survival-of-patients-receiving-radioembolization-for-chemotherapy-refractory-metastatic-colorectal-cancer
#20
Andrew S Kennedy, David Ball, Steven J Cohen, Michael Cohn, Douglas M Coldwell, Alain Drooz, Edward Ehrenwald, Samir Kanani, Fred M Moeslein, Charles W Nutting, Samuel G Putnam, Steven C Rose, Michael Savin, Sabine Schirm, Navesh K Sharma, Eric Wang
BACKGROUND: Patients with liver metastatic colorectal cancer (mCRC) often benefit from receiving (90)Y-microsphere radioembolization (RE) administered via the hepatic arteries. Prior to delivery of liver-directed radiation, standard laboratory tests may assist in improving outcome by identifying correctable pre-radiation abnormalities. METHODS: A database containing retrospective review of consecutively treated patients of mCRC from July 2002 to December 2011 at 11 US institutions was used...
February 2017: Journal of Gastrointestinal Oncology
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