tbuckley/cabot-search huggingface dataset:
NFAT3, a substrate of JNKs, is a negative regulator of Ras-JNK-induced cell transformation
Authors: Ke Yao, Yong-Yeon Cho, Ann Bode, Zigang Dong
Journal: Cancer Research (2007)

431  The c-Jun N-terminal kinases (JNKs) are activated in response to environmental stresses, extracellular stimuli and inflammatory cytokines and are critical for tumor promoter-induced cell transformation and apoptosis. Here, we demonstrated that NFAT3 is a substrate for JNKs and NFAT3 is phosphorylated by JNKs at serines 213 and 217, which are located in the conserved SP motif. The transactivation domain of NFAT3 is located between amino acids 113-260 and includes the phosphorylation target of JNKs. NFAT3 transactivation activity was suppressed in JNK1-/- or JNK2-/- mouse embryonic fibroblasts (MEFs) compared with wildtype MEFs. Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNKs. Mutation of both serines 213 and 217 suppressed NFAT3 transactivation activity and SP600125, a JNKs inhibitor, suppressed NFAT3-induced 3xNFAT-luciferase activity. Knockdown of JNK1 or JNK2 suppressed focus formation in NIH3T3 cells. Importantly, ectopic expression of NFAT3 suppressed AP-1 activity and suppressed focus formation. Furthermore, knockdown of NFAT3 enhanced Ras-JNKs-induced focus formation in NIH3T3 cells. Taken together, these results provide direct evidence for the anti-oncogenic potential of the NFAT3 transcription factor.
Towards a personalised treatment approach for asthma attacks
Authors: Matthew J Martin, Richard Beasley, Tim W Harrison
Journal: Thorax (2020)

Asthma attacks (exacerbations) are common, accounting for over 90 000 UK hospital admissions per annum. They kill nearly 1500 people per year in the UK, have significant associated direct and indirect costs and lead to accelerated and permanent loss of lung function. The recognition of asthma as a heterogeneous condition with multiple phenotypes has revolutionised the approach to the long-term management of the condition, with greater emphasis on personalised treatment and the introduction of the treatable traits concept. In contrast asthma attacks are poorly defined and understood and our treatment approach consists of bronchodilators and systemic corticosteroids. This review aims to explore the current limitations in the description, assessment and management of asthma attacks. We will outline the risk factors for attacks, strategies to modify this risk and describe the recognised characteristics of attacks as a first step towards the development of an approach for phenotyping and personalising the treatment of these critically important events. By doing this, we hope to gradually improve asthma attack treatment and reduce the adverse effects associated with recurrent courses of corticosteroids.
18F-FDG PET/CT Findings in a Rare Myoepithelial Carcinoma Arising in the Parapharyngeal Space
Authors: Chongjiao Li, Yueli Tian, Ying Shen, Bing Wen, Yong He
Journal: Clinical Nuclear Medicine (2020)

Abstract Myoepithelial carcinoma is an exceedingly rare malignant neoplasm that most frequently occurs in the salivary gland. We here report a case of myoepithelial carcinoma in a 57-year-old man. Unenhanced and contrast-enhanced CT scans showed an ill-defined, heterogeneous, contrast-enhancing mass in the left parapharyngeal space, which suggested malignancy. 18 F-FDG PET/CT showed a hypermetabolic mass and multiple FDG-avid lymph nodes in the bilateral cervical regions. An incision biopsy was performed, and the pathological examination confirmed the mass to be a myoepithelial carcinoma.
An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)
Authors: G. R. MacVicar, A. Greco, J. Reeves, J. Maleski, J. Holmlund, L. Leopold
Journal: Journal of Clinical Oncology (2009)

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-X L, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m 2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (&gt;50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed &gt;10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (&gt;20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]
Phase II study of amrubicin (AMR) in patients (pts) with non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy: WJTOG0401
Authors: H. Hayashi, H. Kaneda, I. Okamoto, M. Miyazaki, S. Kudoh, T. Sawa, K. Takeda, S. Negoro, Y. Iwamoto, K. Nakagawa
Journal: Journal of Clinical Oncology (2009)

8059 Background: AMR is a totally synthetic 9-aminoanthracycline and a novel topoisomerase II inhibitor. AMR has shown promising clinical activity for advanced NSCLC as well as SCLC. This trial was conducted to evaluate the efficacy and safety of AMR for pts with NSCLC previously treated with platinum-based chemotherapy. Methods: Eligible pts had a performance status 0 to 1, previous treatment with one platinum-based chemotherapy for advanced NSCLC, and adequate organ function. Pts received AMR 40 mg/m 2 intravenously on days 1–3 every 3 weeks. The primary endpoint was the objective response rate, which determined the sample size based on an optimal two-stage design. With the target activity level of 18% and the lowest response rate of interest set at 5%, 60 eligible patients were required with a 90% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Results: Sixty-one pts (median age, 63 years; range 51–74 years) were enrolled. The median treatment cycles were 2 (range, 1–15). No complete responses and 7 partial responses were observed, giving an overall response rate of 11.5% (95% CI, 4.7–22.2%). Twenty patients (32.8%) had stable disease and 34 patients (55.7%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 44.3% (95% CI, 31.5–57.6%). The median overall survival and 1-year survival rate were 8.5 months and 32.0%, respectively. Grade 3/4 hematological toxicities were neutropenia (82%), anemia (27.9%) and thrombocytopenia (24.6%). Grade 3/4 non-hematological toxicities were anorexia (9.8%), febrile neutropenia (29.5%) and pneumonitis (1.6%). No treatment-related death and cardiac toxicity were observed. Conclusions: AMR exhibits significant activity with manageable toxicities as second-line therapy for advanced NSCLC. [Table: see text]
Bone marrow ablation followed by allogeneic marrow grafting during first complete remission of acute nonlymphocytic leukemia
Authors: SJ Forman, WE Spruce, MJ Farbstein, JL Wolf, EP Scott, AP Nademanee, JL Fahey, T Hecht, JA Zaia, RA Krance, DO Findley, KG Blume
Journal: Blood (1983)
Authors’ response — Delineating a rectum-specific selective resection algorithm: the time is now!
Authors: Neal Shahidi, Sergei Vosko, Michael J Bourke
Journal: Gut (2020)

We thank Dr Santos-Antunes and colleagues for their important letter on resection technique selection for large (≥ 20mm) non-pedunculated colorectal polyps (LNPCPs) in the rectum.1 2 In response, we would like to address a number of critical points.

Santos-Antunes and colleagues correctly point out that a selective resection algorithm, whereby the majority of lesions are treated by endosocpic mucosal resection (EMR), is the optimal management strategy. This is due to EMR’s effectiveness, efficiency, safety and cost savings compared with endoscopic submucosal dissection (ESD) and surgery.3–5 We also agree that the rectum should be viewed as a separate organ, and requires a rectum-specific resection algorithm. This is due to the twofold increased risk of cancer in rectal LNPCPs, and the heightened risk of morbidity and permanent ostomy formation associated with distal colorectal surgery.6 The authors advocate for a universal ESD strategy for the rectum based on their experience. Among …
Cyclophosphamide Based Regimens Compared to Plerixafor-Based Regimens for Stem Cell Mobilization in Patients with Multiple Myeloma Result in Higher CD34+ Cell Yield, Lower Cost and Similar Outcome Post Autologous Transplantation
Authors: Rima M Panchal, Phyllis McKiernan, David Siegel, Scott D. Rowley, David H. Vesole, Tracy Andrews, Andrea Ortega, Alan P Skarbnik, Noa Biran, Joshua R Richter, Nino Aleksidze, Andrew L. Pecora, Andre Goy, Maribel Pereiras, Michele L. Donato
Journal: Blood (2017)
Intelligent difficulty scoring and assistance system for endoscopic extraction of common bile duct stones based on deep learning: multicenter study
Authors: Li Huang, Xiaoyan Lu, Xu Huang, Xiaoping Zou, Lianlian Wu, Zhongyin Zhou, Deqing Wu, Dehua Tang, Dingyuan Chen, Xinyue Wan, Zhongchao Zhu, Tao Deng, Lei Shen, Jun Liu, Yijie Zhu, Dexin Gong, Di Chen, Yanfei Zhong, Feng Liu, Honggang Yu
Journal: Endoscopy (2020)

Abstract Background The study aimed to construct an intelligent difficulty scoring and assistance system (DSAS) for endoscopic retrograde cholangiopancreatography (ERCP) treatment of common bile duct (CBD) stones. Methods 1954 cholangiograms were collected from three hospitals for training and testing the DSAS. The D-LinkNet34 and U-Net were adopted to segment the CBD, stones, and duodenoscope. Based on the segmentation results, the stone size, distal CBD diameter, distal CBD arm, and distal CBD angulation were estimated. The performance of segmentation and estimation was assessed by mean intersection over union (mIoU) and average relative error. A technical difficulty scoring scale, which was used for assessing the technical difficulty of CBD stone removal, was developed and validated. We also analyzed the relationship between scores evaluated by the DSAS and clinical indicators including stone clearance rate and need for endoscopic papillary large-balloon dilation (EPLBD) and lithotripsy. Results The mIoU values of the stone, CBD, and duodenoscope segmentation were 68.35 %, 86.42 %, and 95.85 %, respectively. The estimation performance of the DSAS was superior to nonexpert endoscopists. In addition, the technical difficulty scoring performance of the DSAS was more consistent with expert endoscopists than two nonexpert endoscopists. A DSAS assessment score ≥ 2 was correlated with lower stone clearance rates and more frequent EPLBD. Conclusions An intelligent DSAS based on deep learning was developed. The DSAS could assist endoscopists by automatically scoring the technical difficulty of CBD stone extraction, and guiding the choice of therapeutic approach and appropriate accessories during ERCP.
Detection of Merkel cell polyomavirus in formalin-fixed, paraffin-embedded tissue of Merkel cell carcinoma and its correlation with prognosis
Authors: A. A. Andea, R. Patel, S. Ponnazhagan, S. Kumar, P. DeVilliers, D. Jhala, I. Eltoum, U. Manne, G. Siegal
Journal: Journal of Clinical Oncology (2009)

6027 Background: Polyomaviruses are frequently associated with malignancies in their hosts. Recently, a novel polyoma virus, named Merkel cell polyomavirus (MCV) was identified integrated to the genome of 6 of 10 fresh frozen samples of MCC. These findings suggest an involvement of MCV in the pathogenesis of MCC. Because MCC is a rare tumor, the most readily available tissue is archival formalin-fixed, paraffin-embedded (FFPE) material. In this study we evaluated the presence of MCV in FFPE tissue and correlated its presence with tumor progression. Methods: Representative FFPE specimens from 18 tumors belonging to 14 patients with a diagnosis of MCC were retrieved. Following DNA extraction, we performed PCR using 4 different primer pairs amplifying sequences within the T antigen and VP1 gene of MCV. The identity of the PCR products was confirmed by direct sequencing. For clinical outcome analysis we used our MCC database containing 40 patients from 1997 to 2008 with a median follow-up interval of 20 months (range 1–108 months). Results: We detected MCV amplicons in 8 of 18 analyzed tumors (44.4%) from 7 of 14 cases (50%). PCR products from the T antigen portion of MCV were found in 6 of 18 tumors (33.3%) and from the VP1 gene in 2 of 18 tumors (11.1%). For 3 patients, MCV detection was performed in both the primary and metastatic tumors. In one of these the virus was found in both lesions while in the other 2 only the primary tumor demonstrated the virus. Two- and 5-year survival rates for the MCCs containing the virus were 47.6% and 0% respectively while for the rest of the cases in our database 2- and 5-year survival rates were 61.6% and 40.8% respectively; the difference did not reach however, statistical significance (p = 0.3). Conclusions: We identified MCV sequences in half of the cases analyzed demonstrating the feasibility of this technique in FFPE tissue. We also found that the tumors harboring MCV exhibit a trend for more aggressive behavior compared to the rest of MCCs. These findings suggest that MCV might have an etiologic role in carcinogenesis or tumor progression in MCC. Further studies investigating the biological significance of MCV integration in the human genome and the presence of MCV in other neuroendocrine tumors are warranted. No significant financial relationships to disclose.
Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma
Authors: Charles Marusak, Varsha Thakur, Yuan Li, Juliano T. Freitas, Patrick M. Zmina, Vijay S. Thakur, Mayland Chang, Ming Gao, Jiufeng Tan, Min Xiao, Yiling Lu, Gordon B. Mills, Keith Flaherty, Dennie T. Frederick, Benchun Miao, Ryan J. Sullivan, Tabea Moll, Genevieve M. Boland, Meenhard Herlyn, Gao Zhang, Barbara Bedogni
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line–derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi. Results: MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition. Conclusions: BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
Serum uric acid, influence of sacubitril–valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: <scp>PARAGON‐HF</scp>
Authors: Senthil Selvaraj, Brian L. Claggett, Marc A. Pfeffer, Akshay S. Desai, Finnian R. Mc Causland, Martina M. McGrath, Inder S. Anand, Dirk J. van Veldhuisen, Lars Kober, Stefan Janssens, John G.F. Cleland, Burkert Pieske, Jean L. Rouleau, Michael R. Zile, Victor C. Shi, Martin P. Lefkowitz, John J.V. McMurray, Scott D. Solomon
Journal: European Journal of Heart Failure (2020)
Clinicopathological characterization of chronic lymphocytic leukemia with MYD88 mutations: L265P and non-L265P mutations are associated with different features
Authors: Wen Shuai, Pei Lin, Paolo Strati, Keyur P. Patel, Mark J. Routbort, Shimin Hu, Peng Wei, Joseph D. Khoury, M. James You, Sanam Loghavi, Zhenya Tang, Hong Fang, Beenu Thakral, L. Jeffrey Medeiros, Wei Wang
Journal: Blood Cancer Journal (2020)

Abstract MYD88 mutations in chronic lymphocytic leukemia (CLL) are not well characterized. Earlier reports yielded conflicting results in terms of clinicopathologic presentation and prognostic impact of MYD88 mutations in CLL patients. In addition, the morphological and immunophenotypic features of CLL cases carrying MYD88 mutations have not been explored. Finally, the clinical or biologic implications of the canonical L265P MYD88 mutation vs. mutations in other sites of MYD88 within the context of CLL are also unknown. In this study, a cohort of 1779 CLL patients underwent mutational analysis, and 56 (3.1%) cases were found to have MYD88 mutations, including 38 with L265P mutations (designated here as group A) and 18 with non-L265P mutations (group B). Cases with wild type MYD88 were included as controls. There was no morphological difference in cases with and without MYD88 mutations. Immunophenotypically, cases with mutated MYD88 (both groups A and B) more frequently had an atypical immunophenotype when compared to wild type cases. Group A patients were younger and were associated with variable favorable prognostic factors, including less elevated β2-microglobulin level, negative CD38 and ZAP70, higher frequency of mutated IGHV and isolated del(13q14.3), and lower frequency of del(11q22.3) and mutations of NOTCH1 and SF3B1 . In contrast, group B patients were more similar to CLL patients with wild type MYD88 . There was no difference in time to first treatment when comparing MYD88 -mutated vs. wild type CLL patients before and after stratification according to IGHV mutation status. In summary, MYD88 mutations are uncommon in CLL and cases with L265P mutation have distinctive clinical, immunophenotypic, cytogenetic, and molecular features. There is no significant impact of MYD88 mutations on time to first treatment in CLL.
Multivessel or Culprit Vessel–Only Percutaneous Coronary Intervention for Patients With Acute Myocardial Infarction and Cardiogenic Shock
Authors: Colette DeJong, Rita F. Redberg
Journal: JAMA Internal Medicine (2020)

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THU0494 BACK PAIN, SPINE OSTEOARTHRITIS AND ‘CANDIDATE GENES’ POLYMORPHISM
Authors: N. Pravdyuk, N. Shvyreva, N. Shostak, A. Novikova, E. Zakharova
Journal: Annals of the Rheumatic Diseases (2020)

Background: Low back pain (LBP) and spine osteoarthritis are among the leading health-related causes of disability and reduction in patient quality of life. More recent work suggested that the factors that lead to disc degeneration may have important genetic components. Genetic predisposition has been confirmed by recent findings of associations between degeneration and gene polymorphisms of matrix macromolecules. Objectives: Evaluation of genetic polymorphisms of genes collagen 1A1 (COL1A1), interleikin 1β (IL-1β), interleikin 6 (IL-6), vitamin D receptor (VDR) in patients with LBP, associated with spine osteoarthritis. Methods: We examined 33 patients (men-17, women-16, middle age 28, 7±3,77) with LBP end onset, verified by magnetic resonance imaging (MRI) and 15 controls was carried out. Assessed the intensity of pain syndrome on visual analog scale (VAS, mm) and the nature of its current (IASP, 1994). Polymerase chain reaction and restriction fragments length polymorphism was used to detect the polymorphism of COL1A1 (rs 1800012), IL-1 (rs 1143627), IL-6 (rs 1800795), VDR (rs 1544410). Results: The severity of the pain (VAS) average was 60 mm, all the patients revealed chronic option currents pain syndrome. In 86 % of patients detected changes disc in the form of protrusions and hernias, 17 % of patients had a characteristic reducing the height of the intervertebral disc of lower height disc and osteophytes, arthritis facet joints identified in 20 % of patients in 34% of patients diagnosed changes type Modic II. In 83% of patients with LBP identified homozygous variant allele (GG) Col1A1 gene. The absence of T-alleles in the gene IL 1β in the group of patients was associated with severity of the disease. Carriage of allele in heterozygous AG found in 54% of patients of the main group and was not observed in the control that requires further accumulation of facts. Identified association GG-genotype of IL-6 clinical and instrumental signs of the syndrome Modic-II. Conclusion: These findings may be the reason for the patient-specific approach to diagnosing and treatment of back pain. It proves the necessity of research of genetic polymorphisms in patients with spine osteoarthritis. Disclosure of Interests: : None declared