tbuckley/cabot-search huggingface dataset:
miRNA-497 to enhance the sensitivity of colorectal cancer cells to neoadjuvant chemotherapeutic drug.
Authors: Lin Liu
Journal: Journal of Clinical Oncology (2015)

e22060 Background: The neoadjuvant therapy has significantly improved the outcome of locally advanced resectable T3 rectal cancer patients. Actually, only a portion of patients are sensitive to the preoperative chemoradiation and benefit markedly from this treatment. However, biomarkers for predicting neoadjuvant therapy sensitivity remain unclear. Methods: In this study, through screening of a series of microRNAs dysregulated in colorectal cancer patients, we observed that miRNA-497 expression was down-regulated in tumor tissues of neoadjuvant chemotherapy responders as compared to that in non-responders. Results: MiRNA-497 level was correlated with chemotherapeutic drug 5-fluorouracil (5-FU) sensitivity in colorectal cancer (CRC) cells. Further studies showed that overexpression of miRNA-497 suppressed cell viability and enhanced 5-FU sensitivity in SW480 cells. By contrast, miRNA inhibitors-mediated silence of miRNA-497 promoted cell growth and reduced the sensitivity of LoVo cells to 5-FU. In addition, miRNA-497 targeted Smurf1 in CRC cells and the Smurf1 expression level was dramatically increased in neoadjuvant therapy-resistant patients compared with treatment-sensitive patients. These results indicate that down-regulation of miRNA-497 in colorectal cancer may contribute to the resistance of CRC cells to 5-FU treatment. Conclusions: Thus, miRNA-497 has the potential to be a novel biomarker for predicting the neoadjuvant chemotherapy sensitivity in CRC patients.
Tumour-associated and non-tumour-associated microbiota: Addendum
Authors: Burkhardt Flemer, Maeve Herlihy, Micheal O'Riordain, Fergus Shanahan, Paul W. O'Toole
Journal: Gut Microbes (2018)

In a recent study1 we reported that tissue-associated microbial Co-abundance Groups (CAGs) were differentially associated with colorectal cancer (CRC). Two of the CAGs, which we named Pathogen CAG and Prevotella CAG, were correlated with a gene expression signature indicative of a TH17 response. A TH17 response has been associated with decreased survival in patients with CRC2, and members of the Pathogen CAG such as Fusobacterium nucleatum, Escherichia coli and Bacteroides fragilis have been repeatedly reported to be associated with CRC-development. Thus we hypothesized that the abundance of these CAGs may be associated with poor survival. In this Addendum we extend our analysis of the at-surgery microbiota to microbiota profiles obtained after surgery for CRC which we analyzed in the context of survival data for patients with CRC. Surprisingly we found that high tissue-associated abundance of the previously defined Prevotella- and Pathogen-CAGs at surgery was associated with longer survival. Furthermore, we detected an association of the Bacteroidetes CAG in pre-surgery faecal microbiota with stability of the microbiota after surgery.
SAT-233-Hepatitis C virus reinfection following antiviral treatment among people who inject drugs: A systematic review, meta-analysis, and meta-regression
Authors: Behzad Hajarizadeh, Evan B Cunningham, Heather Valerio, Marianne Martinello, Hannah Reid, Matthew Law, Naveed Janjua, Håvard Midgard, Olav Dalgard, John Dillon, Matthew Hickman, Julie Bruneau, Gregory Dore, Jason Grebely
Journal: Journal of Hepatology (2019)
Expression of thyroid hormone receptor alpha (THRα) isoforms in triple negative breast cancer (TNBC).
Authors: Katarzyna Joanna Jerzak, Jessica Cockburn, Gregory Russell Pond, Robin Hallett, John Hassell, Kathleen I. Pritchard, Sukhbinder K. Dhesy-Thind, Anita Bane
Journal: Journal of Clinical Oncology (2015)

e12082 Background: Thyroid hormones (THs) and their associated receptors may play a role in breast cancer progression given their promotion of cell growth and proliferation. THRα2 expression in ER positive breast cancer has been associated with improved overall survival (OS), but its expression in TNBCs is unknown. Methods: 158 formalin fixed paraffin embedded (FFPE) triple negative tumors were collected from the Juravinski Cancer Center from November 2002 to September 2009. TMA sections of tumors were analysed for the expression of THRα splice variants (THRα1 and THRα2) by immunohistochemistry using the Allred scoring method and assessed in triplicate. The association of THRα1 and THRα2 expression with pathological features, clinical factors and outcomes was evaluated using Spearman correlation coefficients and Cox regression models. Results: Mean ± standard deviation age was 64.4±14.9 years; 77% (n = 122) were grade 3, 22.8% (n = 33) were node positive and 12.3% (n = 19) had stage 3 or 4 disease. 5-year OS was 80.6(95%CI 72.6-86.5) and 5-year recurrence-free survival (RFS) was 73.7(95%CI 65.2-80.4). Treatment consisted of chemotherapy alone (20.3%, n = 31), radiation alone (11.8%, n = 18), chemotherapy and radiation (55.6%, n = 85), or neither (12.4%, n = 19). THRα2 was expressed (Allred score ≥ 5) in 78.0% of patients (n = 117); this level of expression was associated with improved 5-year OS [HR 0.36 (95%CI 0.16-0.83), p = 0.017] and RFS [HR 0.24(0.12-0.47), p < 0.001] in univariable models. THRα1 was expressed (Allred score ≥ 5) in 93.4% of patients (n = 142), but it was not associated with 5-year clinical outcomes. After adjusting for stage, nodal status and treatment, neither THRα1 (p = 0.40) nor THRα2 was significant (p = 0.42) for OS. Conclusions: THRα1 and THRα2 are expressed in the majority of TNBCs. THRα2 expression (Allred score ≥ 5) was associated with improved 5-year OS and RFS, but it was not independently prognostic.
THU-187-Objective evidence of neurocognitive impairment associated with hepatitis C virus infection and of its regression after viral clearance with direct antivirals
Authors: Gloria Vaghi, Matteo Nazzareno Barbaglia, Benedetta Gori, Gionata Strigaro, Michela Emma Burlone, Giacomo Tondo, Rosalba Minisini, Roberto Cantello, Mario Pirisi
Journal: Journal of Hepatology (2019)
Regulation of ezrin tension by S-nitrosylation mediates non-small cell lung cancer invasion and metastasis
Authors: Xiaolong Zhang, Guangming Li, Yichen Guo, Ying Song, Linlin Chen, Qinli Ruan, Yifan Wang, Lixia Sun, Yunfeng Hu, Jingwen Zhou, Bin Ren, Jun Guo
Journal: Theranostics (2019)

Cancer invasion and metastasis depend on accurate and rapid modulation of both chemical and mechanical activities. The S-nitrosylation (SNO) of membrane cytoskeletal cross-linker protein ezrin may regulate the malignant process in a tension-dependent manner. Methods: The level of nitrosylated ezrin in non-small cell lung cancer (NSCLC) tissues and A549 cell line were evaluated by biotin-switch assay. A few cysteine mutated plasmids of ezrin were used to identify active site for SNO. Newly designed ezrin or mutated-ezrin tension probes based on Förster resonance energy transfer (FRET) theory were applied to visually observe real-time tension changes. Cytoskeleton depolymerizing and motor molecular inhibiting experiments were performed to reveal the alternation of the mechanical property of ezrin after SNO. Transwell assays and xenograft mouse model were used to assess aggressiveness of A549 cells in different groups. Fluorescent staining was also applied to examine cellular location and structures. Results: High inducible nitric oxide synthase (iNOS) levels were observed to induce ezrin-SNO, and then promote malignant behaviors of NSCLC cells both in vitro and in vivo. Cys117 was identified as the only active site for ezrin-SNO. Meanwhile, an increased level of ezrin tension was observed after iNOS-induced SNO. Enhanced ezrin tension was positively correlated with aggressiveness of NSCLC. Moreover, Microfilament (MF) forces instead of microtubule (MT) forces played dominant roles in modulating ezrin tension, especially after ezrin nitrosylation. Conclusion: This study revealed a SNO-associated mechanism underlying the mechanical tension of ezrin. Ezrin-SNO promotes NSCLC cells invasion and metastasis through facilitating mechanical transduction from the cytoskeleton to the membrane. These studies implicate the therapeutic potential by targeting ezrin in the inhibition NSCLC invasion and metastasis.
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis
Authors: Benjamin Schattling, Jan Broder Engler, Constantin Volkmann, Nicola Rothammer, Marcel S. Woo, Meike Petersen, Iris Winkler, Max Kaufmann, Sina C. Rosenkranz, Anna Fejtova, Ulrich Thomas, Aparajita Bose, Simone Bauer, Simone Träger, Katharine K. Miller, Wolfgang Brück, Kent E. Duncan, Gabriela Salinas, Peter Soba, Eckart D. Gundelfinger, Doron Merkler, Manuel A. Friese
Journal: Nature Neuroscience (2019)
PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors
Authors: Kensuke Tateishi, Taishi Nakamura, Tareq A. Juratli, Erik A. Williams, Yuko Matsushita, Shigeta Miyake, Mayuko Nishi, Julie J. Miller, Shilpa S. Tummala, Alexandria L. Fink, Nina Lelic, Mara V.A. Koerner, Yohei Miyake, Jo Sasame, Kenji Fujimoto, Takahiro Tanaka, Ryogo Minamimoto, Shigeo Matsunaga, Shigeo Mukaihara, Takashi Shuto, Hiroki Taguchi, Naoko Udaka, Hidetoshi Murata, Akihide Ryo, Shoji Yamanaka, William T. Curry, Dora Dias-Santagata, Tetsuya Yamamoto, Koichi Ichimura, Tracy T. Batchelor, Andrew S. Chi, A. John Iafrate, Hiroaki Wakimoto, Daniel P. Cahill
Journal: Clinical Cancer Research (2019)

Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression.Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo-evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.
Aberrant Hypermetabolism of Benign Uterine Leiomyoma on 18F-FDG PET/CT
Authors: Rafael F. Nunes, Marcelo A. Queiroz, Carlos Alberto Buchpiguel, Filomena Marino Carvalho, Jesus Paula Carvalho
Journal: Clinical Nuclear Medicine (2019)

Leiomyomas are prevalent benign smooth muscle tumors in the uterus, displaying variable degrees of FDG uptake on PET/CT. The glucose metabolism intensity of those lesions relies on biologic features and markedly increased FDG accumulation is more typically related to malignant diseases, as in the case of leiomyosarcomas. Notwithstanding that uterine fibroids typically exhibit mild to moderate FDG uptake, in this article we report a case of unexpectedly intense hypermetabolism of a benign uterine leiomyoma on a PET/CT scan performed for initial staging of a breast cancer patient.
Parotid melanoma of unknown primary site.
Authors: Jeffrey F Scott, Cheryl L. Thompson, Ritva Vyas, Kord Honda, Chad Zender, Rod Rezaee, Pierre Lavertu, Henry B. Koon, Kevin D Cooper, Meg R. Gerstenblith
Journal: Journal of Clinical Oncology (2015)

e20068 Background: Approximately 20% of melanomas occur on the head and neck. The parotid gland and its associated lymph nodes are common metastatic sites for these primary melanomas. Metastatic melanoma to the parotid area carries a poor prognosis and is associated with high rates of distant metastases despite aggressive treatment. Whether this applies to parotid melanoma of unknown primary site is unclear. Methods: We performed the largest analysis to date of parotid melanoma of unknown primary site. We identified a combined 88 patients in our institutional pathology database (n = 45) and in the Surveillance, Epidemiology, and End Results 18 Registries Research Data November 2013 Submission (n = 33) with melanoma of the parotid area (defined as parotid gland or parotid-associated lymph node involvement), diagnosed from 1973 to 2011. Clinicopathologic characteristics and overall survival were compared between patients with parotid melanoma of unknown primary site (PMUP) and known primary site (PMKP). Results: There was no primary site identified in 39 patients (50%). PMUP patients were predominately male (83%, 95% CI 75%-91%), and 56% of cases were diagnosed over age 65 (95% CI 46%-61%). PMUP was found roughly equally in the parotid gland (55%, 95% CI 37%-73%), as compared to its associated lymph nodes (45%, 95% CI 26%-61%). In contrast, PMKP was found more often in the parotid-associated lymph nodes (70%, 95% CI 56%-85%) (p = 0.046). PMUP and PMKP were treated similarly with regards to the rates of parotidectomy, radiation, and cervical lymph node sampling. There was a trend toward higher rates of distant metastases at diagnosis in PMUP (27%, 95% CI 12%-43%), as compared to PMKP (9%, 95% CI 0%-20%) (p = 0.11), but the rate of subsequent metastases was similar (21%, 95% CI 8%-34% for MUP; 26%, 95% CI 12%-40% for MUP) (p = 0.79). The median overall survival was not statistically different in PMUP as compared to PMKP (34 months vs. 21 months, p = 0.56), with a mean follow-up time of 16 and 34 months for the PMUP and PMKP patients, respectively. Conclusions: In the largest analysis of parotid area melanoma of unknown primary site, we found that PMUP occurred principally in men over age 65, and was associated with similar treatments, rates of distant metastases, and overall survival, as compared to PMKP.
SAT-121-Predicting sarcopenia in patients with cirrhosis based on clinical and laboratory parameters using machine learning
Authors: Guido Stirnimann, Maryam Ebady, Bret Hoehn, Isabela Bertoli De Simone, Vera C. Mazurak, Russ Greiner, Puneeta Tandon, Aldo J. Montano-Loza
Journal: Journal of Hepatology (2019)
Clinicopathological characteristics and outcome of advanced ROS1-positive non-small cell lung cancer in Asian patients
Authors: C.Y.X. Kho, D.W.-T. Lim, D.S.W. Tan, W.L. Tan, T. Rajasekaran, A. Jain, C.K. Toh, M.-K. Ang, E.H. Tan, Q.S. Ng
Journal: Annals of Oncology (2019)

Background: ROS1 rearrangement is a rare and distinct molecular subset of non-small cell lung cancer (NSCLC), sensitive to tyrosine kinase inhibitors (TKI) targeting the ROS1 kinase domain. We describe the prevalence, clinicopathological characteristics and clinical outcomes of advanced ROS1 positive NSCLC patients (pts), including concomitant mutations and brain metastases. Methods: We reviewed 1733 consecutive NSCLC pts from the Lung Cancer Consortium Singapore database, reflex tested for ROS1 rearrangement using break-apart fluorescence in situ hybridization. Clinical data including pts characteristics, concomitant mutations, incidence of brain metastasis, response to chemotherapy or TKIs, were retrospectively analyzed. Results: We identified 34 pts (2.0%) with ROS1 positive NSCLC; median age 52 years (range 28-76), 19 males (55.9%), 26 pts (76.5%) never smoked. A patient with stage I was excluded from outcome analysis. All had adenocarcinoma histology. 8 pts (23.5%) had brain metastases at diagnosis and 6 developed brain metastases during treatment. 6 pts (17.6%) harbored concomitant EGFR mutations; 2 (9.1%) had cMET mutations; 1 had EGFR L858R, cMET and ROS1 alterations simultaneously. 8 of 13 pts (61.5%) had PD-L1>1%. Median overall survival (OS) for all pts was 29.3 months (mths). In the first line, 13 pts received chemotherapy; 11 pemetrexed-based with a response rate (RR) of 78% and 2 gemcitabine-based with a RR of 50%. Progression free survival (PFS) was 9.8 mths and OS was 30.6 mths. Ten pts received ROS1 TKIs (9 crizotinib, 1 entrectinib) as first line with RR 80%, PFS 9.9 mths, and OS 23.7 mths. For second line, 7 pts received chemotherapy, 4 were pemetrexed-based (RR 100%) and 3 were gemcitabine-based (RR 0%), 8 pts received ROS1 TKIs (6 crizotinib, 2 ceritinib) (RR 57%). 3 pts with PD-L1>1% received pembrolizumab without objective response. Conclusions: ROS1-positive NSCLC has unique clinicopathological characteristics, high rate of brain metastases and concomitant mutations. Despite effective and durable responses to ROS1 TKI and pemetrexed chemotherapy, optimal treatment sequence remains to be explored and the role of immune checkpoint inhibitors is uncertain. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Gene therapy can cure “bubble boy” disease in babies, researchers find
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Researchers have successfully cured several babies of X linked severe combined immunodeficiency (SCID-X1)—a condition that causes babies to be born without a working immune system, commonly referred to as “bubble boy” disease—by using an experimental gene therapy technique involving HIV.

The study team developed a lentiviral vector, based on HIV, to transfer a correct copy of the defective gene that causes the condition into the bone marrow stem …
THU-024-Methylation signatures in blood show accelerated epigenetic aging in patients with primary sclerosing cholangitis compared to healthy controls
Authors: Michael Trauner, Yevgeniy Gindin, Zhaoshi Jiang, Chuhan Chung, Mani Subramanian, Robert Myers, Aliya Gulamhusein, Kris V. Kowdley, Cynthia LEVY, Zachary Goodman, Michael P. Manns, Christopher Bowlus, Andrew Muir
Journal: Journal of Hepatology (2019)
Abstract PR08: Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity
Authors: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou
Journal: Clinical Cancer Research (2018)

Abstract Our goal is to identify novel targeted therapies for Ewing sarcoma (ES). ES is a devastating malignancy that predominantly affects children and young adults. It is the second most common cancer of the bone, yet in contrast to many other malignancies, survival rates have not improved for decades. For patients with localized disease, no biomarkers exist to predict recurrence or response to chemotherapy. For those with metastatic disease, chemotherapy is largely ineffective, and 5-year survival rates have stagnated at approximately 20%. Thus, there is an urgent need to identify biomarkers that can predict recurrence and response to therapy, as well as identify novel targeted therapies to combat this lethal disease. USP6 is the key etiologic agent in several benign bone and soft tissue tumors (BSTTs), where its chromosomal translocation results in overexpression. USP6 encodes a deubiquitylating enzyme, and our prior studies identified the tyrosine kinase Jak1 as an essential substrate of USP6 during BSTT development. Jak1 levels are dramatically elevated in USP6-overexpressing cells, leading to phosphorylation and activation of STAT transcription factors. We recently discovered that USP6 is also highly expressed in multiple sarcomas, including ES. Since Jak1-STATs play a central in mediating response to interferon (IFN), we hypothesized that USP6 might cause dysregulated IFN signaling in ES. Microarray and RNA-sequencing analysis revealed that USP6 by itself induced an IFN-response gene signature, both in immortalized, patient-derived ES cells and in primary human ES tumors. USP6+ ES cells were found to be exquisitely sensitive to exogenous IFN compared to USP6- ES cells, with both prolonged and heightened STAT1 and STAT3 activation observed. Furthermore, IFN selectively induced apoptosis of USP6+ but not USP6- ES cells. Gene expression analysis confirmed that in USP6+ ES cells, IFN synergistically induced expression of numerous IFN-stimulated genes (ISGs), including the pro-apoptotic ligand TRAIL. CRISPR-mediated depletion of TRAIL completely abrogated IFN-induced death of USP6+ ES cells. In sum, these results identify USP6 as a potential novel biomarker that may predict sensitivity of ES to targeted IFN therapy. This abstract is also being presented as Poster B11. Citation Format: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou. Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR08.