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HIT Cancer

Zhiliang Lu, Yuan Li, Yun Che, Jianbing Huang, Shouguo Sun, Shuangshuang Mao, Yuanyuan Lei, Ning Li, Nan Sun, Jie He
Long non-coding RNAs (lncRNAs) play critical roles in multiple cellular processes in non-small cell lung cancer (NSCLC); however, the involvement of lncRNAs in the transforming growth factor-beta (TGFβ) signaling pathway, the critical tumor cell epithelial-mesenchymal transition (EMT) and metastasis pathway, remains poorly understood. To address this issue, we compared the lncRNAs expression patterns of NSCLC cells treated with and without TGFβ1 treatment. We observed that one of the most prominent hits, TGFβ-induced lncRNA (TBILA), promoted NSCLC progression and was upregulated in tumor tissues...
June 13, 2018: Cancer Letters
Maly Fenelus, Ellinor I B Peerschke
Objectives: To evaluate the use of a pretest probability score (4Ts score) in cancer patients to guide ordering of laboratory screening tests for heparin-induced thrombocytopenia (HIT). Methods: A retrospective chart review was conducted for patients (n = 140) in whom laboratory testing for HIT was requested. 4Ts scores were calculated and correlated with heparin-endogenous platelet factor 4 antibody enzyme-linked immunosorbent assay (ELISA) test results. Results: All patients with a high pretest probability of HIT (4Ts score = 6-7) had positive ELISA results, compared to 26...
June 13, 2018: American Journal of Clinical Pathology
Karin Bauer, Daniela Berger, Christoph C Zielinski, Peter Valent, Thomas W Grunt
In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs...
May 29, 2018: Oncotarget
David W Wolff, Min-Hyung Lee, Mathivanan Jothi, Munmun Mal, Fengzhi Li, Asoke K Mal
Alveolar rhabdomyosarcoma (aRMS) is an aggressive subtype of the most common soft tissue cancer in children. A hallmark of aRMS tumors is incomplete myogenic differentiation despite expression of master myogenic regulators such as MyoD. We previously reported that histone methyltransferase KMT1A suppresses MyoD function to maintain an undifferentiated state in aRMS cells, and that loss of KMT1A is sufficient to induce differentiation and suppress malignant phenotypes in these cells. Here, we develop a chemical compound screening approach using MyoD-responsive luciferase reporter myoblast cells to identify compounds that alleviate suppression of MyoD-mediated differentiation by KMT1A...
May 25, 2018: Oncotarget
Rajdee de Randamie, Gabriel Ángel Martos-Moreno, César Lumbreras, Maria Chueca, Sergio Donnay, Manuel Luque, Rita María Regojo, Marta Mendiola, David Hardisson, Jesús Argente, José C Moreno
BACKGROUND/AIMS: A genomic HABP2 variant was proposed to be responsible for familial nonmedullary thyroid carcinoma (FNMTC). However, its involvement has been questioned in subsequent studies. We aimed to identify genetic HABP2 mutations in a series of FNMTC patients and investigate their involvement in the disease. METHODS: HABP2 was sequenced from 6 index patients. Presence of the variants was investigated in all members of one family. Somatic BRAF and RAS "hotspot" mutations were investigated by the IdyllaTM BRAF Mutation Test and/or Sanger sequencing...
June 12, 2018: Hormone Research in Pædiatrics
Feng Wang, Kyu Ok Jeon, James M Salovich, Jonathan D Macdonald, Joseph Alvarado, Rocco D Gogliotti, Jason Phan, Edward T Olejniczak, Qi Sun, Shidong Wang, DeMarco V Camper, Joannes P Yuh, J Grace Shaw, Jiqing Sai, Olivia W Rossanese, William P Tansey, Shaun R Stauffer, Stephen W Fesik
WDR5 is a chromatin regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed lineage leukemia. Here we describe the discovery of potent and selective WDR5 WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN-site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants < 10 nM and micromolar cellular activity against an AML leukemia cell line...
June 11, 2018: Journal of Medicinal Chemistry
András Demjén, Róbert Alföldi, Anikó Angyal, Márió Gyuris, László Hackler, Gábor J Szebeni, János Wölfling, László G Puskás, Iván Kanizsai
The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure-activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50  = 0...
June 10, 2018: Archiv der Pharmazie
Wookjin Shin, Sang-Kyu Lee, Jeong-Ha Hwang, Jong-Chan Park, Yong-Hee Cho, Eun Ji Ro, Yeonhwa Song, Haeng Ran Seo, Kang-Yell Choi
Although the development of drugs that control Ras is an emerging topic in cancer therapy, no clinically applicable drug is currently available. We have previously utilized knowledge of the Wnt/β-catenin signaling-dependent mechanism of Ras protein stability regulation to identify small molecules that inhibit the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of β-catenin and the need to determine an alternative mechanism of Ras degradation, we designed a cell-based system to screen compounds that degrade Ras independent of the Wnt/β-catenin signaling pathway...
June 6, 2018: Experimental & Molecular Medicine
Yu-Chi Juang, Xavier Fradera, Yongxin Han, Anthony William Partridge
Histidine decarboxylase (HDC) is the primary enzyme that catalyzes the conversion of histidine to histamine. HDC contributes to many physiological responses as histamine plays important roles in allergic reaction, neurological response, gastric acid secretion, and cell proliferation and differentiation. Small-molecule modulation of HDC represents a potential therapeutic strategy for a range of histamine-associated diseases, including inflammatory disease, neurological disorders, gastric ulcers, and select cancers...
June 1, 2018: SLAS Discovery
Poonam Kalhotra, Veera C S R Chittepu, Guillermo Osorio-Revilla, Tzayhri Gallardo-Velázquez
Numerous studies indicate that diets with a variety of fruits and vegetables decrease the incidence of severe diseases, like diabetes, obesity, and cancer. Diets contain a variety of bioactive compounds, and their features, like diverge scaffolds, and structural complexity make them the most successful source of potential leads or hits in the process of drug discovery and drug development. Recently, novel serine protease dipeptidyl peptidase-4 (DPP-4) inhibitors played a role in the management of diabetes, obesity, and cancer...
June 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Lei Zhang, Lei Shi, Shafer Soars, Joshua Kamps, Hang Hubert Yin
Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-κB signaling. Based on two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity...
June 5, 2018: Journal of Medicinal Chemistry
Anna Prossomariti, Harry Sokol, Luigi Ricciardiello
The nucleotide-binding domain leucine-rich repeat containing (NLR) proteins play a fundamental role in innate immunity and intestinal tissue repair. A dysbiotic intestinal microbiota, developed as a consequence of alterations in NLR proteins, has recently emerged as a crucial hit for the development of ulcerative colitis (UC) and colitis-associated cancer (CAC). The concept of the existence of functional axes interconnecting bacteria with NLR proteins in a causal role in intestinal inflammation and CAC aroused a great interest for the potential development of preventive and therapeutic strategies against UC and CAC...
2018: Frontiers in Immunology
Zofia Piotrowska, Justin F Gainor
No abstract text is available yet for this article.
June 4, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Yang Liang, Toma Tebaldi, Kai Rejeski, Poorval Joshi, Giovanni Stefani, Ashley Taylor, Yuanbin Song, Radovan Vasic, Jamie Maziarz, Kunthavai Balasubramanian, Anastasia Ardasheva, Alicia Ding, Alessandro Quattrone, Stephanie Halene
Recurrent mutations in the splicing factor SRSF2 are associated with poor clinical outcomes in myelodysplastic syndromes (MDS). Their high frequency suggests these mutations drive oncogenesis, yet the molecular explanation for this process is unclear. SRSF2 mutations could directly affect pre-mRNA splicing of a vital gene product; alternatively, a whole network of gene products could be affected. Here we determine how SRSF2 mutations globally affect RNA binding and splicing in vivo using HITS-CLIP. Remarkably, the majority of differential binding events do not translate into alternative splicing of exons with SRSF2 P95H binding sites...
June 1, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Natália Bernardi Videira, Fernanda Aparecida Heleno Batista, Artur Torres Cordeiro, Ana Carolina Migliorini Figueira
Peroxisome proliferator-activated receptor beta/delta (PPARß/ δ ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/ δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits...
2018: PPAR Research
Michael J Moore, Nathalie E Blachere, John J Fak, Christopher Y Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-Scharff, Bruno Moltedo, Alexander Y Rudensky, Robert B Darnell
Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in mouse T cells, revealing unanticipated actions in regulating T cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through novel AU-rich sites in coding sequence...
May 31, 2018: ELife
Megan Cully
No abstract text is available yet for this article.
May 30, 2018: Nature Reviews. Drug Discovery
Edward J Calabrese
This paper summarizes the historical and scientific foundations of the Linear No-Threshold (LNT) cancer risk assessment model. The story of cancer risk assessment is an extraordinary one as it was based on an initial incorrect gene mutation interpretation of Muller, the application of this incorrect assumption in the derivation of the LNT single-hit model, and a series of actions by leading radiation geneticists during the 1946-1956 period, including a National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel (Anonymous, 1956), to sustain the LNT belief via a series of deliberate obfuscations, deceptions and misrepresentations that provided the basis of modern cancer risk assessment policy and practices...
May 22, 2018: Environmental Pollution
Wang Peng, Zhi-Yin Sun, Qi Zhang, Sui-Qi Cheng, Shi-Ke Wang, Xiao-Na Wang, Guo-Tao Kuang, Xiao-Xuan Su, Jia-Heng Tan, Zhi-Shu Huang, Tian-Miao Ou
The human proto-oncogene neuroblastoma RAS (NRAS) contains a guanine-rich sequence in the 5'-untranslated regions (5'-UTR) of the mRNA that could form an RNA G-quadruplex structure. This structure acts as a repressor for NRAS translation and could be a potential target for anti-cancer drugs. Our previous studies found an effective scaffold, the quindoline scaffold, for binding and stabilizing the DNA G-quadruplex structures. Here, basing on the previous studies and reported RNA-specific probes, a series of novel p-(methylthio)styryl substituted quindoline (MSQ) derivatives were designed, synthesized and evaluated as NRAS RNA G-quadruplex ligands...
May 25, 2018: Journal of Medicinal Chemistry
Kana Matsumoto, Naoko Udaka, Hisashi Hasumi, Noboru Nakaigawa, Yoji Nagashima, Reiko Tanaka, Ikuma Kato, Masahiro Yao, Mitsuko Furuya
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase (FH) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32-year-old man who underwent nephrectomy for treatment of a solid-cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high-grade tumor cells with enlarged nuclei and eosinophilic nucleoli...
May 24, 2018: Pathology International
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