tbuckley/cabot-search huggingface dataset:
Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC
Authors: Phil A.J. Crosbie, Rajesh Shah, Piotr Krysiak, Cong Zhou, Karen Morris, Jonathan Tugwood, Richard Booton, Fiona Blackhall, Caroline Dive
Journal: Journal of Thoracic Oncology (2016)

Tumor recurrence after surgical resection of NSCLC obstructs long-term disease-free survival in approximately 50% of cases. Our data suggest that combining circulating tumor cell enumeration (as single cells or clusters) in tumor-draining pulmonary vein and peripheral blood (assessed by CellSearch) at the time of NSCLC surgery better identifies those patients at higher risk for lung cancer recurrence than does peripheral circulating tumor cell number alone.
Abstract 4023: Combination therapy with immune checkpoint inhibitor and CCK-receptor blockade increases survival of pancreatic cancer
Authors: Jill P. Smith, Shangzi Wang, Ajina Reham, Sandra A. Jablonski, Louis M. Weiner
Journal: Cancer Research (2016)

Abstract Introduction: Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immune therapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin receptors (CCKRs) are present on pancreatic cancer epithelial cells, fibroblasts of the microenvironment, and lymphocytes. We hypothesized that CCK receptor blockade would improve response to immune checkpoint blockade and survival by promoting influx of tumor infiltrating lymphocytes (TILs) and reducing fibrosis. Methods: Subcutaneous tumors were established using Panc02 murine pancreatic cancer cells (1.0- or 2.0 x10E6) in a syngeneic immune competent mouse model. Three separate experiments were performed with 40 mice each. Mice (C57BL/6) were divided into 4 groups (N = 10 mice each) and treated with PBS (control), a CCKR antagonist (L364,718 or proglumide), an immune checkpoint blockade antibody (PD-1 or CTLA-4; Im-Ab), or the combination of CCKR antagonist and immune checkpoint blockade antibody (combination). Tumor growth and animal survival were evaluated. Tumors were subjected to immunohistochemical staining for TILs, trichrome staining, and flow cytometry. Results: On day 50 after inoculation of 10E6 cells all control mice had died while 42%, 42% and 71% of L364,718, CTLA-4 mice, or combination-treated mice, respectively were alive (p = 0.02). By day 90 all mice died except one in the combination-treated group. In the experiment where mice were injected with 2×10E6 Panc02 cells, survival was also increased in mice receiving a proglumide and PD-1 antibody combination (p = 0.0009). CD8+TILs increased by 3-,6.3-,and 7.5-fold in CCKR antagonist, Im-Ab, and combination therapy, respectively compared to controls (p&amp;lt;0.0001). CD4+ TILs also significantly increased (p = 0.001) in the tumors of mice treated with the combination. Trichrome stain analysis revealed 50% less fibrosis in mice treated with CCKR antagonist compared to PBS controls (p = 0.017). Conclusions: The combination of CCKR antagonism and immune checkpoint blockade antibodies significantly improve survival in a murine model of PDAC. The mechanism is associated with decreased fibrosis in the microenvironment and an accompanying influx of CD8+ and CD4+ TILs. Supported by NCI CA50633, CA51008, and CA194745 Citation Format: Jill P. Smith, Shangzi Wang, Ajina Reham, Sandra A. Jablonski, Louis M. Weiner. Combination therapy with immune checkpoint inhibitor and CCK-receptor blockade increases survival of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4023.
Active surveillance scheme in three Romanian hospitals reveals a high prevalence and variety of carbapenamase-producing Gram-negative bacteria: a pilot study, December 2014 to May 2015
Authors: Dorina Timofte, Carmen Valentina Panzaru, Iuliana Elena Maciuca, Maria Dan, Anca Delia Mare, Adrian Man, Felicia Toma
Journal: Eurosurveillance (2016)

We report the findings of an active surveillance scheme for detection of asymptomatic carriers with carbapenemase-producing Gram-negative bacteria (CP-GNB) in Romanian hospitals. During a pilot study from December 2014 to May 2015, faecal cultures were screened in three hospitals (two large, one medium-size) for patients newly admitted to selected wards or inpatients transferred from other wards to an intensive-care unit. The study revealed a high prevalence of CP-GNB detected in 22/27 and 28/38 of the carbapenem non-susceptible isolates from Hospitals 1 and 3, respectively. CP-GNB identified through faecal screening included NDM-1-producing Serratia marcescens and Klebsiella pneumoniae , OXA-48-producing K. pneumoniae and OXA-23-producing Acinetobacter baumannii. The distribution of the CP-GNB varied between the hospitals, with NDM-1-producing S. marcescens and K. pneumoniae being prevalent in the north-central part of the country and OXA-23/24-producing A. baumannii , OXA-48-producing K.pneumoniae, Morganella morganii and VIM-2-producing Escherichia coli / Pseudomonas aeruginosa detected in the north-east of the country. Conjugation studies showed that carbapenem resistance was transferable and PCR-based replicon typing identified bla NDM-1 on IncFIIs in S. marcescens and K. pneumoniae from Hospital 1 and bla OXA-48 on IncL plasmids in all Klebsiella spp. isolates from Hospitals 1 and 3. Our findings underline the importance of active surveillance for detection of CP-GNB asymptomatic faecal carriers and suggest a likely endemic spread of CP-GNB in Romania.
Abstract 354: Physiologically relevant target engagement using CETSA
Authors: Jakob Karén, Catrine Sioberg, Pawel Niekrasz, Magnus Neumuller, Daniel Martinez Molina
Journal: Cancer Research (2016)

Abstract Targeted therapies are dependent on adequate occupancy and target engagement to reach their efficacy measure. Yet, more than half of novel candidate drugs entering clinical trial stage fail before proof of concept is achieved. Inadequate target engagement is often at the root cause of these failures. Therefore we have developed a versatile label-free method to quantify the target engagement of drugs on their native physiological relevant targets. The method is validated in multiple sample matrices from bench to bedside: in living cells and tissue from rodents and man. CETSA is a patented biophysical method measuring the thermal stability of drug target proteins and the shift induced by their ligands. By quantifying the melting temperature and shift induced by the ligand we can quantify the potency of target engagement. This potency determination then allows filtering of candidate drugs by their ability to engage the target in its physiologically relevant form, in relevant sample formats such as intact cells or tissue. We present a number of applications and readouts of the CETSA method quantifying target engagement of drugs used in the clinic and in development. Furthermore, we show that the target engagement of cyclin dependent kinase inhibitors correlated both to viability and to a dose dependent decrease of a cell cycle activity marker in cellular sample matrices. The biomarker, thymidine kinase activity, was analyzed with the commercially available test DiviTum®. By combining CETSA with DiviTum® in the same samples, it was thus possible to correlate CETSA outcomes to pharmacodynamic effects of a drug. The utility and value of the CETSA method enabling preclinical development of novel drugs is substantiated by the examples included here. Combining quantifications of efficacy with the molecular target engagement of the drug yields an orthogonal dataset, which has a potential to validate the target-mediated efficacy. Such datasets can be generated from early in vitro systems to clinical studies and may reduce the high failure rate in drug development by facilitating the discovery, development and evaluation of novel drugs. Citation Format: Jakob Karén, Catrine Sioberg, Pawel Niekrasz, Magnus Neumuller, Daniel Martinez Molina. Physiologically relevant target engagement using CETSA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 354.
mRNA expression levels and prognostic value of PD1/PDL1 and CTLA4 pathways genes in a large series of 155 bladder tumors.
Authors: Geraldine Pignot, Constance LE Goux, Mathilde Sibony, Sophie Vacher, Nicolas Barry De Longchamps, Marc Zerbib, Diane Damotte, Ivan Bieche
Journal: Journal of Clinical Oncology (2016)

4523 Background: Immunotherapy in bladder cancer seems to give promising results. The purpose of this study is to evaluate the involvement of immune response during bladder carcinogenesis and to compare expression levels in non-muscle invasive bladder cancer (NMIBC) versus muscle-invasive bladder cancer (MIBC). Methods: Expression levels of 3 genes involved in PD1 pathway (PD1, PDL1 and PDL2), 4 genes involved in CTLA4 pathway (CTLA4, CD28, CD80 and CD86) and 27 other immune genes (including LAG3 and TIM3) were assessed by quantitative real time RT-PCR and by immunochemistry in normal and tumoral human bladder samples. Tumors were obtained from 155 patients (25 women and 130 men, mean age 68 years). All patients have signed an informed consent. Pathological tumor staging showed: 71 NMIBC (29 low grade pTa, 14 high grade pTa and 28 high grade pT1), and 84 MIBC (≥ pT2) all of high grade. Results were coupled to a survival analysis. Results: PD1 and PDL1 were significantly overexpressed in MIBC compared to normal bladder tissue (59.5 vs 6.7% and 60.7 vs 0% respectively, p < 0.01), whereas the proportion of overexpression was low in NMIBC (22.5% and 4.2% respectively). Similarly, CTLA4 and one of its ligands CD80 were significantly overexpressed in MIBC as compared to normal bladder tissue (84.5 vs 20.0% and 92.9 vs 6.7% respectively, p < 0.01), whereas CD80 was individually overexpressed in 46.5% of NMIBC without overexpression of CTLA4. There was a high concordance rate between expression levels of the two pathways, according to Spearman test (0.88, p < 0.0001). The results of the molecular analysis were confirmed by immunohistochemistry with a good correlation. There was no correlation between mRNA expression levels of the studied genes and prognosis in terms of relapse / progression for NMIBC and in terms of recurrence-free and overall survival for MIBC. Conclusions: Our results confirm the role of immune checkpoints in bladder carcinogenesis, with a good correlation between RT-PCR and immunochemistry analysis, and opening new therapeutic perspectives, especially for invasive tumors. However, these deregulations do not concern NMIBC and seem not to be associated with survival outcomes.
Patient Navigation in Breast Cancer Treatment and Survivorship: A Systematic Review
Authors: Sharon H. Baik, Linda C. Gallo, Kristen J. Wells
Journal: Journal of Clinical Oncology (2016)

Patient navigation is an intervention approach that improves cancer outcomes by reducing barriers and facilitating timely access to cancer care. Little is known about the benefits of patient navigation during breast cancer treatment and survivorship. This systematic review evaluates the efficacy of patient navigation in improving treatment and survivorship outcomes in women with breast cancer.The review included experimental and quasi-experimental studies of patient navigation programs that target breast cancer treatment and breast cancer survivorship. Articles were systematically obtained through electronic database searches of PubMed/MEDLINE, PsycINFO, Web of Science, CINAHL, and Cochrane Library. The Effective Public Health Practice Project Quality Assessment Tool was used to evaluate the methodologic quality of individual studies.Thirteen studies met the inclusion criteria. Most were of moderate to high quality. Outcomes targeted included timeliness of treatment initiation, adherence to cancer treatment, and adherence to post-treatment surveillance mammography. Heterogeneity of outcome assessments precluded a meta-analysis. Overall, results demonstrated that patient navigation increases surveillance mammography rates, but only minimal evidence was found with regard to its effectiveness in improving breast cancer treatment outcomes.This study is the most comprehensive systematic review of patient navigation research focused on improving breast cancer treatment and survivorship. Minimal research has indicated that patient navigation may be effective for post-treatment surveillance; however, more studies are needed to draw definitive conclusions about the efficacy of patient navigation during and after cancer treatment.
Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis
Authors: Srdan Verstovsek, Taghi Manshouri, Darrell Pilling, Carlos E. Bueso-Ramos, Kate J. Newberry, Sanja Prijic, Liza Knez, Ksenija Bozinovic, David M. Harris, Erika L. Spaeth, Sean M. Post, Asha S. Multani, Raajit K. Rampal, Jihae Ahn, Ross L. Levine, Chad J. Creighton, Hagop M. Kantarjian, Zeev Estrov
Journal: The Journal of Experimental Medicine (2016)

Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process.
Abstract 4853: BMVC specifically binds the major G-quadruplex structure formed in the c-MYC promoter to lower c-MYC levels
Authors: Wenting Liu, Guanhui Wu, Clement Lin, Buket Onel, Ding Chen, Ta-Chau Chang, Danzhou Yang
Journal: Cancer Research (2016)

Abstract The c-MYC proto-oncogene is one of the most deregulated genes in human cancers. Transcriptional repression of c-MYC is considered as one of the attractive strategies in targeting c-MYC. Previous studies revealed that the c-MYC promoter nuclease hypersensitive element (NHE) III1 region, which regulates 80-95% of total c-MYC transcription, can form DNA G-quadruplex (G4) and that stabilization of the c-MYC G4 could repress c-MYC gene expression. We have previously determined the molecular structure of the major G-quadruplex formed in the c-MYC promoter NHE (MycG4), which is an intramolecular parallel-stranded structure. BMVC, a carbazole derivative, was designed as a fluorescent probe for recognizing telomeric G4. However, we found that BMVC binds to MycG4 with much greater affinity and specificity. Cellular studies showed that BMVC was enriched in the nucleus at 48 hr after treatment, leading to markedly reduced c-MYC expression levels. Promoter-driven luciferase assays revealed that BMVC could enhance the inhibitory effects of MycG4, suggesting BMVC can repress c-MYC expression in vivo through stabilization of MycG4. To understand the molecular interactions between BMVC and MycG4, we have determined the molecular structure of the complexes of BMVC with MycG4 by NMR. BMVC appears to bind the 5’-end of the MycG4 with very high affinity, as shown by the slow-exchange binding on the NMR timescale. The structure of the 5’-end complex of BMVC and MycG4 shows that BMVC is paired to the flanking adenine with specific hydrogen bonding interactions, while the BMVC-adenine plane stacks nicely on the 5’-end G-tetrad of MycG4. Compared to the previous MycG4 complex with a quindoline compound, the tighter and more specific binding of BMVC appears to be imparted by the novel arched shape of BMVC and specific pairing recognition of BMVC with the flanking bases of MycG4. BMVC can also bind to the 3’-end of MycG4 with lower affinity to form a second complex. However, the 3’-end complex shows much more dynamic conformation and less specific interactions. Our results indicated that the cellular targets of BMVC include not only telomeric G4, but also the c-MYC promoter G4. Because of the inherent fluorescence and novel binding mode of BMVC, our study provides useful information for future design of improved carbazole-based anticancer agents or specific cellular fluorescent probes, as well as insights into specific recognition of MycG4 by small molecules. Citation Format: Wenting Liu, Guanhui Wu, Clement Lin, Buket Onel, Ding Chen, Ta-Chau Chang, Danzhou Yang. BMVC specifically binds the major G-quadruplex structure formed in the c-MYC promoter to lower c-MYC levels. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4853.
Positive Selection Drives Evolution at the Host–Filovirus Interaction Surface
Authors: Chiara Pontremoli, Diego Forni, Rachele Cagliani, Giulia Filippi, Luca De Gioia, Uberto Pozzoli, Mario Clerici, Manuela Sironi
Journal: Molecular Biology and Evolution (2016)

Filovirus infection is mediated by engagement of the surface-exposed glycoprotein (GP) by its cellular receptor, NPC1 (Niemann-Pick C1). Two loops in the C domain of NPC1 (NPC1-C) bind filovirus GP. Herein, we show that filovirus GP and NPC1-C evolve under mutual selective pressure. Analysis of a large mammalian phylogeny indicated that strong functional/structural constraints limit the NPC1 sequence space available for adaptive change and most sites at the contact interface with GP are under negative selection. These constraints notwithstanding, we detected positive selection at NPC1-C in all mammalian orders, from Primates to Xenarthra. Different codons evolved adaptively in distinct mammals, and most selected sites are located within the two NPC1-C loops that engage GP, or at their anchor points. In Homininae, NPC1-C was a preferential selection target, and the T419I variant possibly represents a human-specific adaptation to filovirus infection. On the other side of the arms-race, GP evolved adaptively during filovirus speciation. One of the selected sites (S142Q) establishes several atom-to-atom contacts with NPC1-C. Additional selected sites are located within epitopes recognized by neutralizing antibodies, including the 14G7 epitope, where sites selected during the recent EBOV epidemic also map. Finally, pairs of co-evolving sites in Marburgviruses and Ebolaviruses were found to involve antigenic determinants. These findings suggest that the host humoral immune response was a major selective pressure during filovirus speciation. The S142Q variant may contribute to determine Ebolavirus host range in the wild. If this were the case, EBOV/BDBV (S142) and SUDV (Q142) may not share the same reservoir(s).
Abstract LB-020: IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B cells
Authors: Karsten Sauer, Claire Conche, Hyun-Yong Jin, Kelly Bethel, Stephanie Rigaud, Luise Westernberg, Sabine Siegemund, Changchun Xiao
Journal: Cancer Research (2016)

Abstract Accounting for ∼4% of all cancers in the US, Non-Hodgkin Lymphoma (NHL) is the most prevalent blood cancer. Diffuse large B-cell Lymphoma (DLBCL) is the most common and aggressive type of NHL. Here, we identify inositol-trisphosphate (IP3) 3-kinase B (Itpkb) as a novel tumor suppressor whose deficiency triggers DLBCL in mice. We found that aging Itpkb-/- mice die prematurely with anemia and splenomegaly. 15% of these mice showed multiorgan-infiltration with neoplastic germinal-center phenotype B cells reminiscent of DLBCL. Itpkb-/- B cell lymphomas are mono-or oligoclonal, transplantable, and constitutively hyperactivate the oncogenic phosphoinositide 3-kinase (PI3K) signaling pathway. Growth of Itpkb-/- B cell lymphoma xenografts in immunodeficient mice is sensitive to treatment with PI3K or mTOR inhibitors. In humans, subsets of DLBCL patients carry Itpkb missense mutations, deletions or copy number reductions. Additionally, Itpkb expression is altered in several other hematopoietic and non-hematopoietic human cancers. We propose that Itpkb suppresses tumors by producing inositol-tetrakisphosphate (IP4), a soluble analog of the PI3K product phosphatidylinositol-trisphosphate (PIP3). We and others have previously shown that IP4 antagonism with PIP3 for Akt effector kinase binding prevents excessive Akt/mTORC1 signaling in hematopoietic cells. Our new results suggest that this mechanism prevents oncogenic PI3K signaling in the B cell lineage and possibly in other cell types. Thus, Itpkb might be a novel biomarker for tumor aggressiveness or prognosis, and Itpkb activating drugs or IP4 might have therapeutic potential. This work was supported by NIH grants AI070845 and GM100785 to KS, The Leukemia &amp; Lymphoma Society Scholar Award 1440-11 to KS, the AAI Careers in Immunology Fellowship Program to SR, DFG Fellowship SI 1547/1-1 to SS, and an ARC fellowship to CC. Citation Format: Karsten Sauer, Claire Conche, Hyun-Yong Jin, Kelly Bethel, Stephanie Rigaud, Luise Westernberg, Sabine Siegemund, Changchun Xiao. IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-020.
A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis
Authors: S Verstovsek, M Talpaz, E Ritchie, M Wadleigh, O Odenike, C Jamieson, B Stein, T Uno, R A Mesa
Journal: Leukemia (2016)

NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK–signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1–2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.