tbuckley/cabot-search huggingface dataset:
Abstract 5526: Tumor suppressive role ofBMI-1through inhibition of JAK-STAT signaling in leukemia
Authors: Yuk Man Lam, Stephen Sze Yuen Lam, Anskar Yu Hung Leung, Ray Kit Ng
Journal: Cancer Research (2017)

Abstract BMI-1, which is one of the core components of polycomb repressive complex 1, is frequently found deregulated in patients with hematological disorders. In last decades, researchers concordantly agree that BMI-1 mediates tumorigenesis of leukemia stem cells through p16INK4A leukemogenic pathway. However, accumulating evidences contradict the idea that BMI-1 solely plays an oncogenic role in tumorigenesis. It has been shown BMI-1 depletion favors the development of myelofibrosis in mice; whereas high BMI-1 expression suppressed colony forming ability of MLL-ENL-transformed bone marrow and correlated with higher survival in some cancers. In this study, we hypothesized that BMI-1 plays a tumor suppressive role, which is independent of the regulation of INK4A-ARF locus, in human leukemia. BMI-1 was over-expressed in a panel of myeloid and lymphoid lineage leukemia cells, including HL-60, MV4-11, MonoMac-6, SEM, Nalm-20 and RS4;11. We observed no deregulation of p16INK4A and p14ARF genes by BMI-1, suggesting the regulation of INK4A-ARF locus is independent of BMI-1 modulation in leukemia cells. Nevertheless, over-expression of BMI-1 resulted in significant reduction of leukemia cell proliferation. It is noted that constitutively active JAK-STAT signaling pathway is crucial to leukemia cell survival. By modulation of BMI-1 level, we demonstrated suppression of the activated JAK-STAT signaling pathway in most of the leukemia cell lines with the exception of MonoMac-6 and RS4;11. This is in agreement with the high sensitivity to ruxolitinib, a JAK-STAT inhibitor, in all the tested leukemia cell lines except RS4;11. Importantly, we showed that BMI-1 over-expression could sensitize RS4;11 cells to reduce cell proliferation under ruxolitinib treatment. These results suggest that higher efficacy of ruxolitinib treatment could be achieved under a condition of high cellular level of BMI-1. We further demonstrated that ruxolitinib treatment was more effective in a cohort of AML patient samples (n = 25) with a context of higher BMI-1 expression (p &amp;lt; 0.05). Altogether, our results suggest that BMI-1 functions as a tumor suppressor gene via inhibition of the JAK-STAT signaling pathway. The endogenous level of BMI-1 could be served as an indicator for the effective treatment of JAK-STAT-dependent leukemia cells using ruxolitinib. Citation Format: Yuk Man Lam, Stephen Sze Yuen Lam, Anskar Yu Hung Leung, Ray Kit Ng. Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5526. doi:10.1158/1538-7445.AM2017-5526
Protein tyrosine phosphatase inhibition abrogates the effect of Cr(VI) on the effectors of the G1/S checkpoint through mechanisms involving Akt
Authors: Madhu Lal, Steven Patierno, Dong-Soon Bae, Susan Ceryak
Journal: Cancer Research (2007)

5202  Certain forms of hexavalent chromium [Cr (VI)] are human carcinogens. Previous work in our lab has shown that a broad range protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SOV) partially abrogated Cr (VI) - induced growth arrest and induced cell cycle checkpoint override, which was coincident with Akt activation. The aim of the present study was to determine the correlation between the Cr (VI)-induced Akt downregulation on the localization and expression of various effectors of the G1/S checkpoint (p21, p27, Cyclin D1 and phospho Rb) and the role of PTP inhibition in this effect. HLFs were treated with 0 -6µM of Cr (VI), with and without 10µM SOV, fixed on 8-well chambered coverslips and incubated with a primary antibody to either p21, p27, Cyclin D1 or phospho Ser 807/811 Rb followed by treatment with a secondary antibody conjugated to a fluorochrome, Alexafluor 488. These experiments were also performed with HLFs transfected with Akt-KD (kinase dead) and constitutively active Myr-Akt plasmids as well as HLFs in which Akt1 was silenced with siRNA. Cr (VI) caused nuclear localization of p27 as early as 4h after exposure. The addition of SOV alone had no effect on nuclear localization, but caused the nuclear export of p27 in the presence of Cr (VI), which was maximum at 24 hours. In cells in which Akt was knocked down by siRNA or transfected with the Akt-KD plasmid, p27 was localized in the nucleus after Cr(VI) exposure, even in the presence of SOV. Conversely, in cells transfected with the Myr-Akt plasmid, there was no nuclear localization of p27 in the presence of Cr(VI). Finally, Cr(VI) induced a punctuate nuclear staining of pRb which was abrogated by PTP inhibition. The total cellular levels of p27, p21, Cyclin D1, pRb and pSer473 Akt were determined by Western blotting techniques. Cr (VI) induced a dose-dependant decrease in the expression of p27, pSer 473 Akt, Cyclin D1 and pRb after 24h exposure, while SOV abrogated a decrease only in pSer 473 Akt and pRb expression. In conclusion, Akt activation is necessary for the cytosolic retention of p27 by SOV, which may be responsible in part for the previously observed activity of this PTP inhibitor in overriding Cr (VI)-induced checkpoint arrest and this effect appears to be independent of p27 protein expression. The bypass of cell cycle checkpoint arrest by Akt activation in the face of genotoxic damage could increase genomic instability and metastasis, which is a hallmark of neoplastic progression. This study was supported by NIH grants CA107972 to SC and E505304 and E509961 to SRP.
Abstract 12008: C-Reactive Protein Value on Admission is Incremental to GRACE Score in Predicting Mortality in Acute Coronary Syndromes
Authors: Simone Persampieri, Federica Valli, Ludovico Sabatelli, Giulia Ferrante, Francesca Bursi, Marco Centola, Diego Castini, Stefano Carugo
Journal: Circulation (2018)

Introduction: C-reactive protein (CRP) is an acute phase protein that becomes detectable in the circulation in response to inflammatory cytokines that usually increase in myocardial infarction. To ...
Blinatumomab Treatment in Korean Adult Patients with Relapse/Refractory Acute Lymphoblastic Leukemia
Authors: Sung-Hoon Jung, Deok-Hwan Yang, Jae-Ho Yoon, Seok Lee, Dae Sik Kim, Se Ryun Lee, Sung-Hyun Kim, Ji Hyun Lee, Soo-Mee Bang, Youngil Koh, Ho-Young Yhim, Sang Kyun Sohn, Ik-Chan Song, Hong-ghi Lee, June-Won Cheong, Yunsuk Choi, Ho-Jin Shin
Journal: Blood (2017)
Identifying TRKA and TRKB specific pathways in neuroblastoma through phosphoproteomic analysis.
Authors: Samuel Louis Volchenboum, Kolbrun Kristjansdottir, Ilana Bergelson, Saira Khan, Garrett M. Brodeur
Journal: Journal of Clinical Oncology (2012)

e20008 Background: Neuroblastoma is the most common solid tumor found in children and is difficult to treat given its genetic and clinical heterogeneity. The tyrosine kinase receptor, TrkB, is often co-expressed with the MYCN oncogene in high-risk tumors, whereas the TrkA receptor is most often found expressed in low-risk, non-MYCN amplified samples. There are differences in the gene expression profiles of TrkB- and TrkA-over-expressing cell lines, but they do not explain the phenotypic variation. We hypothesize that differences in protein translation and post-translational modifications have profound downstream effects on cellular signaling and disease phenotype. Methods: We performed quantitative proteomics using stable isotope labeling, phosphopeptide enrichment, and tandem mass spectrometry on parental SY5Y neuroblastoma cells and cell lines stably transfected with either TrkA or TrkB. Receptors were activated with NGF or BDNF and activation was inhibited with CEP-701 (Lestaurtinib), a selective tyrosine kinase inhibitor, currently in clinical trials. Samples were separated by gel electrophoresis, digested with trypsin, and applied to the mass spectrometer for protein identification. Results: We have performed quantitative phosphoproteomic analysis and compared protein expression levels and patterns in TrkA overexpressing, TrkB overexpressing, and parental SY5Y cells. The TrkA and TrkB receptors were activated with NGF and BDNF ligands, respectively, as evidenced by increased phosphorylation of ERK and AKT, with inhibition by CEP-701. Changes in protein abundance and pathway activation following both ligand binding and inhibition are being determined by quantitative phosphoproteomic analysis, and TrkA-specific and TrkB-specific differences will be presented. Conclusions: As current genomic techniques may underestimate the differences in protein expression, proteomic profiling holds great promise for describing how post-translational modifications such as phosphorylation can affect tumor phenotype. Our work may reveal key elements of TRK signaling pathways important in neuroblastoma tumorigenesis, and may lead to the identification of novel targets for therapy development.
The hidden cost of colonoscopy including cost of reprocessing and infection rate: the implications for disposable colonoscopes
Authors: Sara Larsen, Anthony Kalloo, Susan Hutfless
Journal: Gut (2019)

Multiple studies have documented a high rate of contaminated colonoscopes after reprocessing. Contaminated reusable colonoscopes may increase the risk of device-related patient infections. As disposable colonoscopes enter the market, they may play a role in infection prevention and may be cost-effective at some facilities or in high-risk patients. Using a micro-costing approach, this study found that the cost per colonoscopy including purchase, maintenance and reprocessing ranges from US$188.64 at high volume centres (3000 annual procedures) to US$501.16 at low volume centres (1000 annual procedures). Accordingly, per-procedure capital costs range from US$87.48 to US$262.45; repair costs range from US$68.77 to US$206.32; cleaning supplies and labour costs US$32.39 and infections requiring hospitalisation cost US$20.12 to US$46.52. As disposable colonoscopes enter the market, low volume centres are most likely to achieve cost savings. Determining if post-procedural infection rates differ with reusable vs disposable colonoscopes is needed.

### In more detail

Each year more than 15 million colonoscopy procedures are performed in the USA and the number is increasing.1 Colonoscopy is generally thought to be safe; however, patients are sometimes hospitalised afterwards, due to infections that may have been transmitted via contaminated colonoscopes (MAUDE Adverse Event Report).2 3 Colonoscopy-related infections and complications have been reported in multiple studies, although at lower rates compared with endoscopic retrograde cholangiopancreatography (ERCP).1 4 5 Guideline revisions in response to endoscope-associated infections require healthcare institutions to invest more resources in the high-level disinfection process or conversion to sterilisation (Ofstead et al ).5,6 Despite colonoscopy being the highest volume GI procedure, the true cost and time associated with reusable colonoscopes are unknown. The purpose of this study was to explore real-world costs associated with …
Endoscopic resection of early-stage SMAD4 juvenile polyposis does not prevent disease spreading in the stomach
Authors: Etienne Baldysiak, Nicolas Benech, Laura Calavas, Jérôme Rivory, Pierre-Marie Lavrut, Jean-Christophe Saurin, Mathieu Pioche
Journal: Endoscopy (2019)

To the best our knowledge, juvenile polyposis with a SMAD4 germline mutation is a rare disease [1] [2], and its precise endoscopic aspect has been described in the colon [3] but not in the stomach. The natural history of this particular polyposis has not been well described.
Cost of Pediatric Severe Sepsis Hospitalizations
Authors: Erin F. Carlton, Ryan P. Barbaro, Theodore “Jack” Iwashyna, Hallie C. Prescott
Journal: JAMA Pediatrics (2019)

Cost of Pediatric Severe Sepsis HospitalizationsIn 2005, the most recent year for which nationwide estimates are available, the total costs of pediatric severe sepsis hospitalizations were estimated at $4.8 billion ($5.8 billion in 2016 dollars). 1Since then, there has been increasing attention to severe sepsis, revision of sepsis treatment guidelines, and a growing prevalence of children with medical complexity who account for the large portion of health care expenditure, hospitalization stays, and readmissions. 2,3Thus, we sought to measure the current costs of pediatric severe sepsis and understand the association of complex chronic conditions with sepsis hospitalization costs.Methods | We studied pediatric hospitalizations (in patients 19 years or younger) in the 2016 Nationwide Readmissions
A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer.
Authors: Mercedes Martinez Villacampa, Jaume Capdevila, Jose Luis Manzano, Carles Pericay, Ramon Salazar, Carlos López-López, Ferran Losa, M. José Safont, Auxiliadora Gomez, Vicente Alonso, M. Pilar Escudero, Javier Gallego Plazas, Javier Sastre, Cristina Gravalos Castro, Sebastiano Biondo, Amalia Palacios, Enrique Aranda
Journal: Journal of Clinical Oncology (2012)

3571 Background: The addition of bevacizumab (BEV) to capecitabine (CAP)-based chemoradiation (CRT) has shown encouraging efficacy in locally advanced rectal cancer (LARC), in nonrandomized studies. This randomized phase II study investigated the effect of adding BEV to preoperative CAP-based CRT in patients (pts), with LARC. Methods: The primary end point was pathologic complete response (pCR). A two-stage design was used. Assuming a minimum pCR rate of at least 15% in one of the arms, a difference between the two arms of 10%, and accepting a probability of correct selection of 87%, 41 pts per arm were needed. Patients with LARC (Stages II-III assessed by MRI) and ECOG PS &lt;2 were randomized to concurrent radiotherapy 45Gy/25f/5 weeks + CAP (825mg/m²/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm A) or the same schedule without BEV (arm B). Surgery was scheduled 6-8 weeks after completing CRT. Results: 90 pts were randomized (arm A/B: 44/46). Patient’s characteristics were well balanced between both arms: male 61%, median age 62 years, median distance from anal verge 7 cm, T3 79%, N+ 87%. 40 (91%)/43 (93%) of pts (arm A/B) finalized the planned CRT + surgery treatment. Overall grade 3-4 toxicity rates were 18 % and 13% (arm A/B, p=0.50); no grade 3-4 hematological toxicity was reported. Postoperative complications were 19(43%)/17(37%)(arm A/B). Efficacy data on patients who actually underwent surgery are reported in the table. Conclusions: The addition of BEV to CAP-based preoperative CRT has shown to be feasible and safe in the local control of LARC. No differences in pCR were observed and longer follow-up is needed to assess the impact on survival endpoints. [Table: see text]
Mechanism of chemosensitization of drug-resistant MM cell lines by anit- IgG3-avidin fusion protein targeting the transferrin receptor: inhibition of the Akt pathway and downregulation of XIAP and Bcl-xL
Authors: Eriko Suzuki, Gustavo Helguera, Tracy Daniels, Manuel Penichet, Benjamin Bonavida
Journal: Cancer Research (2007)

4866  Patients with multiple myeloma (MM) are treated with chemotherapy and recently with the proteasome inhibitor Bortezomib. However, there are patients who either do no respond to such treatments or develop resistance suggesting the need of novel therapeutic approaches. We have developed an anti-human transferrin receptor IgG3-avidin fusion protein (anti-hTfR .IgG3-Av) to target the TfRwith the objective of targeting the transferrin receptor on tumor cells and induceinducing tumor cell killing with a biotinyalated toxin. We have found, however, that anti-hTfR .IgG3-Av treatment alone could inhibit tumor cell proliferation and was also cytotoxic to some but not all MM cell lines studied.. We hypothesized that the cytotoxic potential of anti-hTfR .IgG3-Av may alter the anti-apoptotic pathway of tumor cells reducingand reduce the anti-apoptotic threshold and sensitizingthus can sensitize tumor cells to apoptosis by chemotherapeutic drugs. This hypothesis was examined with IM-9 and 8226S 2 MM cell lines both of which are resistant to CDDP-induced apoptosis. Treatment of MM cells with various suboptimal concentrations of anti-hTfR .IgG3-Av followed by treatment with CDDP (non-biotinylated) resulted in significant potentiation of apoptosis and synergy was achieved. We examined the underlying mechanism of synergy. Cell treatment with anti-hTfR .IgG3-Av resulted in significant mitochondrial depolarization, activation of caspase 9 and inhibition of the anti-apoptotic gene products XIAP and Bcl-xL. The combination treatment with CDDP enhanced these effects and resulted in caspase 3 activation and apoptosis. The inhibitioninhibiton of Bcl-xL and XIAP by anti-hTfR .IgG3-Av suggested that it may inhibit survival pathways that regulate the transcription of these gene products. It has been reported that Bcl-xL and XIAP are transcriptionally regulated by the NF-κB pathway and Bcl-xL function is regulated by the Akt pathway through phosphorylation of Bad and the inhibition of Bad-Bcl-xL complexes. In addition, the Akt pathway cross-talks and also regulates the NF-κB pathway. We demonstrate that treatment of MM cells with anti-hTfR.IgG3-Av inhibited the constitutively activated Akt pathway suggesting its role in the downstream regulation of XIAP and Bcl-xL and anti-hTfR .IgG3-Av-mediated chemosensitization. These findings demonstrate that the combination of anti-hTfR .IgG3-Av and CDDP results in activation of the mitochondrial pathway for apoptosis, inhibition of XIAP and Bcl-xL which leads to synergistic apoptosis. InhibitorsInhibitors of the Akt pathway have been used clinically (example: rapamycin) and many rapamycin analogues are currently in clinical trials. The inhibition of the Akt pathway by anti-hTfR .IgG3-Av provides a novel Akt inhibitor and its potential use in cancer therapy.
Seeing the Forest for the (Arterial) Tree: Vascular Pruning and the Chronic Obstructive Pulmonary Disease Pulmonary Vascular Phenotype
Authors: Jason Weatherald, David Montani, Marc Humbert
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

and neutrophilia.This is competence without comprehension, which is entirely justifiable, as it represents powerful, data-driven medicine.Would the identification of particular metabolites or their fragments by GC-MS in exhaled air by itself qualify for unraveling the critical pathobiological pathways in relation to eosinophilic or neutrophilic inflammation?This is unlikely, as the "big brothers" of this technology, such as transcriptomics and proteomics, are much closer to the mechanistic networks and are delivering at present (3, 4).The prospect of using GC-MS in this context is therefore twofold.First, when associating the present VOCs with accompanying RNA and protein profiles, it might become feasible to indirectly establish any transcriptomic or proteomic fingerprints of asthma by noninvasive analysis of exhaled VOCs.Then breathomics is used for rapidly recognizing elaborate biological phenotypes, as has been done by Brinkman and colleagues for electronic nose (eNose) profiles against sputum transcriptomics profiles (8) (data in online supplement).Second, GC-MS data from the present study can also be used for tailoring crossreactive sensors for eNoses toward their most discriminative and evidence-based combination for establishing eosinophilic or neutrophilic inflammation (9).Notably, eNoses have also been trained and validated in discriminating eosinophilic and neutrophilic inflammation with high accuracy, regardless of the clinical diagnosis of asthma or chronic obstructive pulmonary disease (8, 10).The advantage of the latter technology is that it can be linked to big online databases and cloud computing, providing real-time results in the doctor's office (www.breathbase.org).The article by Schleich and colleagues ( 7) presents a landmark study on the validation of exhaled VOCs in the inflammatory profiling of asthma.This is needed for type 2 and increasingly also for non-type 2 asthma phenotypes.Ongoing clinical tailoring of breathomics is definitely bringing data-driven, precision medicine to the point of care.
A novel non-HLA-restricted cellular immune assay for monitoring patient (pt) response to targeted immunotherapeutics
Authors: K. Manson, K. E. Dolan, J. Marshall, H. Kaufman, G. P. Mazzara, T. J. Schuetz
Journal: Journal of Clinical Oncology (2006)

2567 Background: Many therapeutic cancer vaccines are designed to elicit T-cell immunity. In vitro monitoring of pt response is limited by the HLA-restriction of ELISPOT assays. We report a novel, non-restricted assay for measuring immune responses generated by PANVAC-VF, which comprises 2 recombinant viral vectors in a heterologous prime-boost immunization regimen. Each vector contains genes encoding the tumor antigens CEA and MUC-1, and 3 immunologic costimulatory molecules B7.1, LFA-3, and ICAM-1. The safety of PANVAC-VF was tested in a Phase 1 study of 10 pts with advanced pancreatic cancer (ASCO 2005 abstr 2576). Methods: Peripheral blood mononuclear cells (PBMCs) were drawn at baseline and each subsequent timepoint (∼2 wks after each injection) to measure cellular immune responses. PBMCs were separated from whole blood over a Ficoll gradient; isolated PBMCs were frozen in liquid nitrogen until analysis. A monkey breast cancer cell line (CMMT 110/C1) was infected with PANVAC-F or control fowlpox recombinant. On Day 2, PBMCs were incubated 10:1 with infected CMMT 110/C1 cells, and the mixtures co-cultivated for 72 h. Supernatants were assayed for interferon γ production. Results: Of 8 pts with PBMCs sufficient for testing, 5 developed an antigen-specific immune response to CEA and/or MUC-1. In general, interferon γ production steadily increased with repeat boosting immunizations. Cellular depletion experiments suggest that the result is dependent on CD4+ cells, allowing analysis of samples from all pts, unlike the ELISPOT, which is restricted to HLA-A2 peptide presentation. Preliminary analysis suggests a positive correlation of immune response with overall survival. Conclusions: We developed a novel, non-restricted cellular assay to assess immune response to a targeted immunotherapeutic, PANVAC-VF. Five of 8 assayed pts developed an antigen-specific cellular immune response. Pt numbers are small, but there appears to be a correlation between immune response and overall survival. This assay will be used for samples from a randomized Phase 3 study in pancreatic cancer and a randomized Phase 2 study in prostate cancer, generating a large data set of immune responses from all pts. [Table: see text]