tbuckley/cabot-search huggingface dataset:
SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells
Authors: Xiaoling Kuai, Long Li, Ran Chen, Kangjunjie Wang, Min Chen, Binghai Cui, Yuxue Zhang, Junqiang Li, Hongwen Zhu, Hu Zhou, Jianfei Huang, Jun Qin, Zhiwei Wang, Wenyi Wei, Daming Gao
Journal: Cancer Research (2019)

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. SIGNIFICANCE: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.
18F-Choline PET/CT Detected Skull Base Paraganglioma
Authors: Alexander D. Harbourne, Kevin M. Bradley
Journal: Clinical Nuclear Medicine (2019)

Abstract We present a case of a right skull base paraganglioma detected using 18 F-choline PET/CT in a 63-year-old man. The 18 F-choline PET/CT scan was performed to assess a known prostate cancer. In addition, the scan demonstrated a mildly choline-avid (SUV max , 3.8) tumor within the carotid sheath of the right skull base, extending through the jugular foramen to the cerebellomedullary and cerebellopontine angles. 18 F-choline may provide a superior alternative to FDG in imaging paragangliomas of the skull base because, unlike FDG, there is no significant 18 F-choline uptake in the adjacent brain.
Human Mesenchymal Stem Cell-Treated Regulatory CD23<sup>+</sup>CD43<sup>+</sup> B Cells Alleviate Intestinal Inflammation
Authors: Xiaoyong Chen, Chuang Cai, Dijing Xu, Qiuli Liu, Shuwei Zheng, Longshan Liu, Gang Li, Xiaoran Zhang, Xiaoping Li, Yuanchen Ma, Li Huang, Jieying Chen, Jiahao Shi, Xin Du, Wenjie Xia, Andy Peng Xiang, Yanwen Peng
Journal: Theranostics (2019)

Rationale: Mesenchymal stem cells (MSCs) have been demonstrated to ameliorate inflammatory bowel disease by their actions on multiple immune cells, especially on regulatory B cells (Breg cells). However, the phenotypes and functions of human MSCs (hMSCs)-treated Breg cell subsets are not yet clear. Methods: Purified B cells were cocultured with MSCs and the phenotypes and immunomodulatory functions of the B cells were analyzed by FACS and proliferation assays in vitro. Also, a trinitrobenzenesulfonic acid-induced mouse colitis model was employed to detect the function of MSC-treated Breg cells in vivo. Results: We demonstrated that coculturing with hMSCs significantly enhanced the immunomodulatory activity of B cells by up-regulating IL-10 expression. We then identified that a novel regulatory B cell population characterized by CD23 and CD43 phenotypic markers could be induced by hMSCs. The CD23+CD43+ Breg cells substantially inhibited the inflammatory cytokine secretion and proliferation of T cells through an IL-10-dependent pathway. More significantly, intraperitoneal injection of hMSCs ameliorated the clinical and histopathological severity in the mouse experimental colitis model, accompanied by an increase in the number of CD23+CD43+ Breg cells. The adoptive transfer of CD23+CD43+ B cells effectively alleviated murine colitis, as compared with the CD23-CD43- B cells. Treatment with CD23+CD43+ B cells, and not hMSCs, substantially improved the symptoms of colitis in B cell-depleted mice. Conclusion: the novel CD23+CD43+ Breg cell subset appears to be involved in the immunomodulatory function of hMSCs and sheds new light on elucidating the therapeutic mechanism of hMSCs for the treatment of inflammation-related diseases.
The IL15 Superagonist Complex ALT-803 Potently Enhances the Proliferative Capacity and Activity of in Vitro Expanded Natural Killer Cells
Authors: Tarun K. Garg, Katie Stone, Amy Greenway, Carolina D. Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Joshua Epstein, Brian A Walker, Hing C Wong, Emily K Jeng, Niraj Shrestha, Faith E Davies, Gareth J. Morgan, Frits van Rhee
Journal: Blood (2017)
Subclinical Hypothyroidism
Authors: Bernadette Biondi, Anne R. Cappola, David S. Cooper
Journal: JAMA (2019)

<h3>Importance</h3> Subclinical hypothyroidism, defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT<sub>4</sub>) affects up to 10% of the adult population. <h3>Observations</h3> Subclinical hypothyroidism is most often caused by autoimmune (Hashimoto) thyroiditis. However, serum thyrotropin levels rise as people without thyroid disease age; serum thyrotropin concentrations may surpass the upper limit of the traditional reference range of 4 to 5 mU/L among elderly patients. This phenomenon has likely led to an overestimation of the true prevalence of subclinical hypothyroidism in persons older than 70 years. In patients who have circulating thyroid peroxidase antibodies, there is a greater risk of progression from subclinical to overt hypothyroidism. Subclinical hypothyroidism may be associated with an increased risk of heart failure, coronary artery disease events, and mortality from coronary heart disease. In addition, middle-aged patients with subclinical hypothyroidism may have cognitive impairment, nonspecific symptoms such as fatigue, and altered mood. In the absence of large randomized trials showing benefit from levothyroxine therapy, the rationale for treatment is based on the potential for decreasing the risk of adverse cardiovascular events and the possibility of preventing progression to overt hypothyroidism. However, levothyroxine therapy may be associated with iatrogenic thyrotoxicosis, especially in elderly patients, and there is no evidence that it is beneficial in persons aged 65 years or older. <h3>Conclusions and Relevance</h3> Subclinical hypothyroidism is common and most individuals can be observed without treatment. Treatment might be indicated for patients with subclinical hypothyroidism and serum thyrotropin levels of 10 mU/L or higher or for young and middle-aged individuals with subclinical hypothyroidism and symptoms consistent with mild hypothyroidism.
Zinc inhibits mitochondrial aconitase expression in prostate cancer cells
Authors: Ziqiang Yu, Leslie C. Costello, Pei Feng, Renty B. Franklin
Journal: Cancer Research (2006)

95  The normal prostate gland accumulates the highest levels of zinc and citrate of any tissue in the body. The very high zinc level inhibits mitochondrial aconitase (mACO) activity which contributes to the mechanism of citrate accumulation by the prostate. Thus, the high zinc and citrate levels characteristic of the normal prostate are causatively related. Moreover, both zinc and citrate levels decrease in prostate cancer, which suggest that loss of the ability to accumulate zinc is necessary for the development and progression of prostate cancer. Since previous studies showed that zinc inhibits mACO activity, in this study we investigated the effect of zinc on mACO levels in prostate cancer cells and in normal prostate tissues. Wild type PC-3 cells, and cells that stably over express a zinc transporter, ZIP1, were cultured in medium with10% FBS. Rat prostate, kidney and liver tissues were resected and digested to prepare isolated cell suspensions. The cells were treated with 1 μM sodium pyrithione, 20 μM ZnCl2 or 20 μM ZnCl2 + sodium pyrithione for 1 - 3 hours. Mitochondria and whole cell lysates were prepared by standard, published procedures. The mACO protein level and cytochrome c level were determined by Western blot using specific antibodies. PC-3 cells stably transfected with a luciferase reporter, which contains a 1411 bp (-1415/-5) 5′ fragment the mACO gene, were also treated as above and mACO promoter activity analyzed by luciferase reporter assay. Mitochondrial aconitase and cytochrome c levels were dramatically decreased by ZnCl2 + pyrithione treatment in wild type PC-3 cells, and PC-3 cells that over express the hZip1 zinc transporter. Sodium pyrithione alone had no effect on mACO or cytochrome c levels. The levels of mACO and cytochrome c in normal rat prostate, kidney and liver tissues were unchanged by the same treatment. We previously showed that zinc treatment of PC-3 cells induced apoptosis and release of cytochrome c. Therefore, we determined if the decrease in mACO following zinc treatment was the result of the release of m-aconitase from mitochondria or altered mACO gene expression. Results of luciferase assays showed that zinc treatment decreased luciferase expression by the mACO promoter luciferase construct. In addition, zinc treatment did not result in the apperance of mACO in the cytosol fraction. Results of these studies indicate that zinc treatment of PC-3 cells results in a decrease in mACO and cytochrome c levels. The mechanism of the zinc effect on mACO is inhibition of transcription, while an increase in mitochondrial permeability is likely the cause of decreased cytochrome c. In addition, the effect of zinc on mACO may be specific to cancer cells and the loss this zinc effect maybe important in the development and progression of prostate cancer. (Supported by NIH grants CA079903 and DK42839)
Phase II study of rituximab + CHOP followed by <sup>90</sup>Y-ibritumomab tiuxetan in patients with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499)
Authors: M. R. Smith, H. Chen, L. Gordon, J. Foran, B. Kahl, R. Advani, R. D. Gascoyne, E. Weller, S. J. Horning
Journal: Journal of Clinical Oncology (2006)

7503 Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate, 90 Y-ibritumomab tiuxetan ( 90 Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC &gt;2,500/μl; platelets &gt;100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg 90 Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and 90 Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% &gt;1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After 90 Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after 90 Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After 90 Y-RIT, responses improved in 15 of 37 pt with &lt;CR/CRu: PR to CR/CRu (n = 12) and SD to CR (n = 1) or PR (n = 2) for a final response rate of 84% and CR rate of 45%. Conclusions: 90 Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF. [Table: see text]
Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection
Authors: Mathieu Angin, Stevenn Volant, Caroline Passaes, Camille Lecuroux, Valérie Monceaux, Marie-Agnès Dillies, José Carlos Valle-Casuso, Gianfranco Pancino, Bruno Vaslin, Roger Le Grand, Laurence Weiss, Cecile Goujard, Laurence Meyer, Faroudy Boufassa, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión
Journal: Nature Metabolism (2019)
T-cell lymphoma secondary to checkpoint inhibitor (CPI) used for other malignancies.
Authors: Kartik Anand, Joe Ensor, Shruti Pandita, Sai Ravi Pingali, Shubham Pant, Cassian Yee, Madeleine Duvic, Tej Pandita, Carlos A. Torres-Cabala, Roberto N. Miranda, Youli Zu, Swaminathan Padmanabhan Iyer
Journal: Journal of Clinical Oncology (2019)

88 Background: Wartewig et al. (Nature 2017) proved in a preclinical mouse model that anti-PD1 therapy could cause T-cell lymphoma. T-cell lymphoma as an adverse event of CPIs has never been reported. A 75-year-old male with h/o urothelial carcinoma presented with lung metastasis of adenocarcinoma of unknown primary that showed PDL1 staining 5% of cells. Patient was treated with carboplatin &amp; paclitaxel. For progressive disease, the patient received Pembrolizumab. After 4 cycles of CPI he developed lymphocytosis and lymphadenopathy and diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), with bone marrow (BM) involvement. Patient died before receiving any treatment for lymphoma. We hypothesized that CPI caused clonal expansion of T cells. Methods: We performed T-cell receptor (TCR) sequencing by Immunoseq assay in biopsy specimens. We queried FDA Adverse Events Reporting System (FAERS) and VigiBase databases for T-cell lymphoma/leukemia, PTCL, NOS, Mycosis Fungoides, Anaplastic Large &amp; Cutaneous T-cell Lymphoma as an adverse event (AE) secondary to nivolumab, pembrolizumab or ipilimumab. Results: Through TCR sequencing we identified single clonal expansion before PD1 therapy in lung (0.008%) to 11% in bone marrow and 40% in lymph node (post treatment samples). Additional targeted exome sequencing of the lymphoma revealed a TET2 mutation. We conclude that anti-PD1 caused clonal expansion of the T cells harboring TET2 mutation leading to T-cell lymphoma. Findings of FARES and VigiBase review are shown in the Table. Conclusions: T-cell lymphoma is a rare complication of CPIs, with high mortality (20%). Long term follow up of patients receiving CPIs is needed. [Table: see text]
Arrhythmogenic Syncope in a Soldier First-Responder Reveals Channelopathy—Last Response for the First Responder?
Authors: Caroline E. Murphy, Colin M. Kenny, Emilio Fentanes
Journal: JAMA Internal Medicine (2019)

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Prevalence of Infective Endocarditis in Enterococcus faecalis Bacteremia
Authors: Anders Dahl, Kasper Iversen, Niels Tonder, Nis Hoest, Magnus Arpi, Morten Dalsgaard, Mahtab Chehri, Lars L. Soerensen, Soren Fanoe, Soeren Junge, Ulla Hoest, Nana Valeur, Trine K. Lauridsen, Emil Fosbol, Thomas Hoi-Hansen, Niels E. Bruun
Journal: Journal of the American College of Cardiology (2019)
Analysis of real-world PD-L1 IHC testing for clinical use in patients across multiple tumor types.
Authors: Gabriel S Krigsfeld, Emily Prince, Kim Zerba, Vladislav Chizhevsky, Josette William Ragheb, James William White
Journal: Journal of Clinical Oncology (2019)

151 Background: A number of programmed death ligand 1 (PD-L1) IHC diagnostic tests have been approved by the FDA to guide treatment with programmed death-1/PD-L1 inhibitors. We evaluated PD-L1 assay utilization and concordance across all tumor types, including melanoma (MEL) and squamous cell carcinoma of the head and neck (SCCHN), using real-world cancer samples tested at a single reference laboratory in the United States. Methods: 55,652 samples with clinical characteristics were provided by Symphony Health Solutions. NeoGenomics Laboratories, Inc assessed PD-L1 expression using the Dako PD-L1 IHC 28-8 or 22C3 pharmDx, or Ventana PD-L1 SP142 assay tests between October 2015 and April 2018, according to the manufacturers’ protocols at the time of the study. Clinical characteristics were matched to PD-L1 test results using unique identifiers. Data were analyzed by BioStat Solutions, Inc. Results: 61,568 tests from 55,652 patients were included. Across all 61,568 tests, 88.8% were carried out with 22C3, 9.8% with 28-8, and 1.4% with SP142. The 28-8 and 22C3 pharmDx assays showed high analytical concordance in all 3113 matched samples with PD-L1 expression data for both assays (OPA = 96.2%, Spearman’s r = 0.96; Table). The failure rate across all tests was 3.5%, and 96.6% of patients had a quantifiable test result. Average test turnaround time was 3.1 days, with a 9.1-fold increase in total number of tests performed between Q4 2015 and Q1 2018 (from 1163 to 10,544). Subgroup analyses for 678 patients (1.2%) with MEL and 270 patients (0.5%) with SCCHN will be presented. Conclusions: Despite an increased demand for PD-L1 testing in the US, most patients received a result in 2–4 days. These real-world analytical data support the potential interchangeability of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in clinical practice for assessing tumor cell membrane PD-L1 expression across tumor types, and provide context on the evolution and adoption of PD-L1 testing for patients with cancer. [Table: see text]
IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed By Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT)
Authors: Anastasios Stathis, Anna Gregorini, Remy Gressin, Lorella Orsucci, Aurore Perrot, Monica Tani, Bertrand Coiffier, Gerardo Musuraca, Romain Guieze, Dario Marino, Guido Gini, Angela Ferrari, Emmanuel Gyan, Franck Morschhauser, Francesca Palombi, Federica Cavallo, Steven Le Gouill, Herve Tilly, Flavia Salvi, Annarita Conconi, Maria Giuseppina Cabras, Enrico Capochiani, Catello Califano, Anna Lia Molinari, Alessandro Pulsoni, Nicoletta Ielmini, Stefano Luminari, Franco Cavalli, Emanuele Zucca, Catherine Thieblemont
Journal: Blood (2017)
Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout
Authors: Yusuke Kawamura, Hirofumi Nakaoka, Akiyoshi Nakayama, Yukinori Okada, Ken Yamamoto, Toshihide Higashino, Masayuki Sakiyama, Toru Shimizu, Hiroshi Ooyama, Keiko Ooyama, Mitsuo Nagase, Yuji Hidaka, Yuko Shirahama, Kazuyoshi Hosomichi, Yuichiro Nishida, Ippei Shimoshikiryo, Asahi Hishida, Sakurako Katsuura-Kamano, Seiko Shimizu, Makoto Kawaguchi, Hirokazu Uemura, Rie Ibusuki, Megumi Hara, Mariko Naito, Mikiya Takao, Mayuko Nakajima, Satoko Iwasawa, Hiroshi Nakashima, Keizo Ohnaka, Takahiro Nakamura, Blanka Stiburkova, Tony R Merriman, Masahiro Nakatochi, Sahoko Ichihara, Mitsuhiro Yokota, Tappei Takada, Tatsuya Saitoh, Yoichiro Kamatani, Atsushi Takahashi, Kokichi Arisawa, Toshiro Takezaki, Keitaro Tanaka, Kenji Wakai, Michiaki Kubo, Tatsuo Hosoya, Kimiyoshi Ichida, Ituro Inoue, Nariyoshi Shinomiya, Hirotaka Matsuo
Journal: Annals of the Rheumatic Diseases (2019)

Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F ) and one suggestive locus (rs12980365 of ZNF724 ) at the genome-wide significance level (p&lt;5.0×10 – 8 ). The present study also identified the loci of ABCG2 , ALDH2 and SLC2A9 . One of them, rs671 of ALDH2 , was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci ( CNTN5 , MIR302F and ZNF724 ) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.