tbuckley/cabot-search huggingface dataset:
The ubiquitin ligase Smurf1 regulates cell polarity and protrusion formation by targeting the small GTPase RhoA for degradation.
Authors: Hong-Rui Wang, Yue Zhang, Barish Ozdamar, Abiodun A. Ogunjimi, Evguenia Alexandrova, Gerald H. Thomsen, Jeffrey L. Wrana
Journal: Cancer Research (2004)

2432  The small Rho family GTPases are key regulators of cytoskeletal dynamics that control cell shape, polarity and motility. Recent studies show that PAR6, which binds to atypical protein kinase C zeta (PKCζ), is key effector of Cdc42 and Rac1 and important for cell transformation, cell polarity, and regulation of epithelial tight junctions. However, it is still not clear how these biological functions are controlled by the Cdc42/Rac1-PAR6-PKCζ. The Smurf C2-WW-HECT domain ubiquitin ligases were recently shown to regulate TGFbeta signal transduction by targeting Smad signaling molecules for degradation. Here we demonstrated that Smurf1, a C2-WW-HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transformed morphology and motility of a tumor cell. Overexpression of Smurf1 in Mv1Lu cells induced large number of dynamic protrusions, while moderate levels of expression of Smurf1 in NIH3T3 cells disrupted cell polarity. We also found that Smurf1 interacted with PKCζ, an effector of the Cdc42/Rac1-PAR6 polarity complex, and colocalized at cellular protrusions. The localization of Smurf1/ PKCζ complex was dependent on the PKCζ activity, while the expression of Smurf1 was also crucial for PKCζ localization at the protrusions. Furthermore, we showed that Smurf1 targeted RhoA for degradation through ubiquitin dependent proteasome pathway and therefore controlled the local level of RhoA, which is important for the local actin cytoskeleton dynamics. Thus, Smurf1 may link the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signalling during dynamic membrane movements.
Recommendations for cytogenomic analysis of hematologic malignancies: comments from the Francophone Group of Hematological Cytogenetics (GFCH)
Authors: Florence Nguyen-Khac, Audrey Bidet, Lauren Veronese, Agnes Daudignon, Dominique Penther, Marie-Bérengère Troadec, Christine Lefebvre, Marina Lafage-Pochitaloff
Journal: Leukemia (2019)
AMG 655, a monoclonal antibody agonist directed against Death Receptor 5, induces apoptosis in human colon carcinoma cell lines and its therapeutic potential is enhanced in combination with chemotherapeutic agents
Authors: Jason Wall, Matt colloton, Justin Huard, Brad Sevetson, Chang-Pin Huang, Yang Pan, Brian Gliniak
Journal: Cancer Research (2008)

1326  Death Receptor 5 (DR5), a member of the tumor necrosis factor family of receptors, can transduce an apoptotic signal following Tumor necrosis factor Related Apoptosis Inducing Ligand (Apo2L/TRAIL) stimulation or treatment with agonistic anti-DR5 antibodies. AMG 655 is a fully human monoclonal agonistic antibody (IgG1) directed against human DR5 and is currently in clinical development. AMG 655 can activate capsases 3/7 and induce apoptosis in the human colon carcinoma cell lines Colo 205 and HCT-15 in vitro. Both cell lines could be further sensitized to AMG 655-induced apoptosis by the addition of the chemotherapeutic agents irinotecan (CPT-11) or 5-fluorouracil (5-FU). Combining AMG 655 with CPT-11 or 5-FU in vitro resulted in a significant enhancement in caspase 3/7 activity relative to either agent alone. Enhanced anti-tumor activity of AMG 655 in combination with CPT-11 or 5-FU was also observed in vivo. Treatment of Colo 205 tumor-bearing SCID mice with a sub-optimal dose of AMG 655 (2.5 μg/dose x 3) in combination with CPT-11 (20 mg/kg and 80 mg/kg) significantly (p=0.02 and p=0.01, respectively) enhanced the anti-tumor effect of AMG 655 relative to AMG 655 or CPT-11 alone. Combining AMG 655 with 5-FU (20 or 40 mg/kg) resulted in enhanced anti-tumor activity and the regression of tumor xenografts for up to 47 days. Treatment of SCID mice bearing HCT-15 tumor xenografts with AMG 655 (25 μg/dose x 3) in combination with CPT-11 (20 or 80 mg/kg) or with 5-FU at 40 mg/kg significantly (p
Survival rates in elderly patients with heart failure
Authors: Tahira Khan, Ahmed Fathelrahman Awadalla
Journal: European Journal of Heart Failure (2019)

We read with interest the article by Jones et al.1 which analysed the survival rates of patients in the community with chronic heart failure (HF). It is notable that in patients aged ≤ 65 years, the rates of survival were almost 10% and 30% better at 1 and 5 years, respectively, when compared to those aged ≥ 75 years. This may be due to co-morbidities in the older population, but another possibility may be due to these patients not being put on adequate HF medications. Molnar et al.2 have shown that the survival benefit of beta-blockers in chronic HF could be extrapolated to elderly patients with advanced chronic kidney disease (CKD). In a retrospective cohort study involving 5862 elderly patients with advanced CKD, the group showed reduced all-cause mortality with beta-blocker use. Similarly, Martínez-Milla et al.3 performed a single-centre, observational cohort study on 390 patients aged ≥75 years with CKD who were in receipt of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and mineralocorticoid receptor antagonists (MRAs). Their findings showed that ACEi/ARB treatment was associated with fewer cardiovascular events, whilst MRAs did not reduce the number of this nor influence total mortality. Anaemia, which is common in elderly HF patients, is associated with a worse prognosis, as shown by Savarese et al.4 The group looked at the Swedish Heart Failure registry data of 49 985 patients and found that anaemia is associated with worse prognosis in both HF with preserved ejection fraction and HF with reduced ejection fraction. These patients have received more aggressive treatment with intravenous iron infusions over the last few years. It would be useful to have data, if available from the papers in this meta-analysis, on this correlation and whether treatment improved prognosis, especially in the elderly. With newer agents such as empagliflozin not yet in wider usage but shown to improve mortality in HF,5 it would be interesting to see how future data will be affected, particularly in the elderly population who also tend to have more advanced diabetes due to its progression over time.
Enzymatic activity of prostate-specific antigen (PSA) in prostate cancer and human bone-metastasizing prostate cancer LNCaP cells
Authors: Wilhelmina C. Duivenvoorden, Nicholas G. Escott
Journal: Cancer Research (2005)

5617  Patients with prostate cancer frequently have a poor prognosis as a result of the spread of cancer to bone. The presence of tumour cells frequently stimulates osteoblastic activity resulting in increased bone mass in these patients. The serum PSA (prostate-specific antigen) test is widely used for the early diagnosis, staging and monitoring of prostate cancer. There is evidence suggesting that the serine protease activity of PSA could be involved in the osteoblastic activity observed in bone metastasis from prostate cancer. PSA is expressed as a prepro-protein. The predominant form of PSA in serum is PSA bound to α1-antichymotrypsin (ACT). Substrates of PSA include semenogelin, fibronectin, and laminin. On the other hand, in tumour tissue an inverse correlation between Gleason score and PSA staining intensity has been shown by immunohistochemistry. This discrepancy between serum and tissue PSA underlines the need for clarification of the biological role of PSA in prostate cancer, which is still unknown. The objectives of this study were to determine the prevalent form of PSA in human prostate adenocarcinoma samples and the enzymatic activity towards various substrates of PSA. Tumour samples were obtained from prostate cancer patients undergoing prostatectomy, snap-frozen in liquid nitrogen, and homogenized in 125 mM Tris, 10% SDS. Sera were obtained from prostate cancer patients with PSA values above 100 ng/ml. For comparison recombinant PSA and PSA found in the conditioned media (CM) of human prostate cancer LNCaP cells were used. Homogenates of tumour samples and sera were subjected to SDS-PAGE followed by Western blotting using antibodies against PSA and PSA bound to ACT. PSA activity was determined in tumour homogenates, serum, and LNCaP-CM using a synthetic substrate (S-2586). Samples (5 μg of tumour homogenate, 1 μl of serum, or 20 μl of CM) were incubated with 0.5 mM S-2586 and absorbance at 405 nm was measured spectrophotometrically. Degradation experiments were carried out by incubating samples in the presence of 2.5 μg human fibronectin or 5 μg laminin for 4 hrs at 37 °C, followed by separation by 5-20% SDS-PAGE and staining with Coomassie Blue. Our results show that in most tumour homogenates and in the LNCaP-conditioned media the majority of the PSA was present in the 31 kDa form (pro-PSA). In the sera the predominant form of PSA was PSA-ACT. All prostate cancer homogenates showed activity towards S-2586, however one sample (R256) demonstrated very high activity. Tumour sample R256 was also capable of degrading fibronectin and laminin, which was inhibitable by the addition of 200 μM Zn2+ but only in part by 100 μg/ml TPCK. Fibronectin enzymography showed proteolytic activity at 29 kDa further confirming the presence of active PSA. (This research is supported by the Canadian Institutes of Health Research and the Northern Cancer Research Foundation.)
Biodegradable zwitterionic polymer membrane coating endowing nanoparticles with ultra-long circulation and enhanced tumor photothermal therapy
Authors: Shaojun Peng, Boshu Ouyang, Yongzhi Men, Yang Du, Yongbin Cao, Ruihong Xie, Zhiqing Pang, Shun Shen, Wuli Yang
Journal: Biomaterials (2019)
Gemtuzumab Ozogamicin in <i>NPM1</i>-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study
Authors: Richard F. Schlenk, Peter Paschka, Julia Krzykalla, Daniela Weber, Silke Kapp-Schwoerer, Verena I. Gaidzik, Claudia Leis, Walter Fiedler, Thomas Kindler, Thomas Schroeder, Karin Mayer, Michael Lübbert, Mohammed Wattad, Katharina Götze, Heinz A. Horst, Elisabeth Koller, Gerald Wulf, Jan Schleicher, Martin Bentz, Richard Greil, Bernd Hertenstein, Jürgen Krauter, Uwe Martens, David Nachbaur, Maisun Abu Samra, Michael Girschikofsky, Nadezda Basara, Axel Benner, Felicitas Thol, Michael Heuser, Arnold Ganser, Konstanze Döhner, Hartmut Döhner
Journal: Journal of Clinical Oncology (2019)

PURPOSE High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all- trans-retinoic acid with or without GO. The early ( P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( P = .005), with no difference in the cumulative incidence of death ( P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication–negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.
Association between interpregnancy interval and subsequent stillbirth in 58 low-income and middle-income countries: a retrospective analysis using Demographic and Health Surveys
Authors: Akshay Swaminathan, Deshayne B Fell, Annette Regan, Mark Walker, Daniel J Corsi
Journal: The Lancet Global Health (2019)

BackgroundAbout 3 million stillbirths occur each year, 98% of which are in low-income and middle-income countries (LMICs). Interpregnancy interval is a key risk factor of interest, because it is modifiable. We aimed to investigate whether there is a causal relationship between the length of interpregnancy interval and risk of subsequent stillbirth.MethodsWe used Demographic and Health Surveys (2002–18) from 58 LMICs to study reproductive histories of women and to identify livebirths and stillbirths in the preceding 5 years. Countries were selected on the basis of the availability of interpregnancy interval data and other covariates of interest (age, education, urban or rural residence, and wealth) in surveys done since 2002. Exclusion criteria were being nulliparous, having missing parity data, and not having had at least two births (livebirth or stillbirth) in the 5 years before the survey. We combined two analytic approaches: one that analyses intervals between all births and another that analyses intervals within mothers. We report stratified estimates for the first, second, and third intervals, controlling for all past birth outcomes and intervals in a 5-year period, and other socioeconomic covariates. We also explored effect heterogeneity across key cohort subgroups.FindingsBetween July, 1997, and April, 2018, we identified 716 478 births from 338 223 women in 123 Demographic and Health Surveys from 58 LMICs, of which 9647 were stillbirths. Intervals of less than 6 months were associated with an increased risk of stillbirth in the between-mother models when considering the first interval (risk difference [RD] 0·0096, 95% CI 0·008–0·011). This association was slightly attenuated when considering only the second interval (RD 0·0054, 95% CI 0·0010 to 0·0099) and substantially attenuated when considering only the third interval (0·0007, −0·037 to 0·039). Within-mother modelling showed a null association with intervals of 24–59 months when considering the first and second (RD 0·007, 95% CI −0·001 to 0·016) and first and third (0·040, −0·422 to 0·501) intervals.InterpretationAlthough interpregnancy intervals of less than 12 months were associated with increased risk of stillbirth, these effects were attenuated when considering second and third intervals, suggesting the association in the first interval might not be causal. Future studies should use generalisable cohorts with longitudinal data, and report estimates stratified by birth order.FundingCanadian Institutes of Health Research.
Healthy Diet and Risk of Dementia in Older Adults—Reply
Authors: Ilianna Lourida, Elzbieta Kuzma, David J. Llewelyn
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Art in Endoscopy: “The Whale”
Authors: Arne Bleijenberg, Barbara Bastiaansen
Journal: Endoscopy (2019)

This is a sessile serrated lesion after submucosal dye injection, just before endoscopic mucosal resection. The prominent adenomatous nodule reveals progression to cytologic dysplasia, which is a late step in the serrated neoplasia pathway to colorectal cancer. Often, an adenomatous nodule in a polyp is mistaken for a small tubular adenoma by the endoscopist, while the surrounding nondysplastic area of sessile serrated lesion is easily overlooked because of its subtle appearance. This might lead to resection of only the adenomatous nodule, leaving in situ the rest of the lesion.
Durability and Efficacy of Tricuspid Valve Repair in Patients Undergoing Left Ventricular Assist Device Implantation
Authors: Yaron D. Barac, Alina Nicoara, Muath Bishawi, Jacob N. Schroder, Mani A. Daneshmand, Nazish K. Hashmi, Eric Velazquez, Joseph G. Rogers, Chetan B. Patel, Carmelo A. Milano
Journal: JACC Heart Failure (2019)
Abstract A42: Single-cell RNA-seq analysis of human pancreatic ductal adenocarcinoma identifies a novel cell type expressing the intestinal stem cell marker OLFM4
Authors: Manisha Rao, Alice Nemajerova, Jinyu Li, Mei Gao, Ki Oh, Richard Moffit, Joseph Kim, George Georgakis, Aaron Sasson, Agnieszka Bialkowkska, Scott Powers
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenomcarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of 8%. To determine the composition of different cell types in PDAC, we performed single-cell RNA-sequencing (scRNA-seq) analysis of two resected patient tumors. Nine distinct cell types were identified: (1) ductal carcinoma cells expressing mutant KRAS, (2) normal pancreatic islet cells, (3) B-lymphocytes, (4) macrophages, (5) mast cells, (6) nerve cells, (7-8) two types of cancer-associated fibroblasts (CAFs), and (9) a previously unidentified epithelial type with distinctly high expression of OLFM4 and CRISP3. Histologic analysis of human PDAC and chronic pancreatitis (CP) tissue sections confirmed the presence of this distinct cell type and furthermore demonstrated that it corresponded to inflamed/injured ducts and early pancreatic intraepithelial neoplasms (PanINs) but that actual PDACs did not express OLFM4. CRISP3 was not always expressed in this new cell type, but the expression of OLFM4 was always detected in these histologic structures. This distinct pancreatic epithelial cell type was also observed in mouse models for chronic pancreatitis and in mutant-KRAS induced PanINs. We hypothesize that inflammation-induced OLFM4 expression helps drive PanIN formation, and that its expression could be exploited for early PDAC detection. We are currently performing functional studies using organoids to address the role that OLFM4 might play in generation of this distinct cell type. Citation Format: Manisha Rao, Alice Nemajerova, Jinyu Li, Mei Gao, Ki Oh, Richard Moffit, Joseph Kim, George Georgakis, Aaron Sasson, Agnieszka Bialkowkska, Scott Powers. Single-cell RNA-seq analysis of human pancreatic ductal adenocarcinoma identifies a novel cell type expressing the intestinal stem cell marker OLFM4 [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A42.
Advances in implant therapy in North America: Improved outcomes and application in the compromised dentition
Authors: Hanae Saito, Mary Beth Aichelmann‐Reidy, Thomas W. Oates
Journal: Periodontology 2000 (2019)

Abstract Advances in dental implant therapy have strengthened our understanding of the management of the implant‐soft tissue interface, with site‐specific implications ranging from marginal tissue management and esthetics to immediate placement and restoration, and extend to patient‐level implications of systemic conditions. The advancements in implant therapy have placed an increased emphasis on patient‐centered outcomes. In this paper, the following conclusions can be drawn: improvements in both esthetics and long‐term maintenance have been guided by the study of the marginal peri‐implant tissues leading to innovations in implant design along the implant‐abutment interface. Patient expectations for simple and realistic time intervals for treatment have promoted the use of immediate implant placement and restoration. The expansion of implant therapy offers implant options for patients with medical conditions, with one in particular, diabetes mellitus a focus of this paper. Studies on patients with diabetes are supporting the development of evidence‐based treatment considerations with broader application and greater benefits for the use of implant therapy across a larger patient population. This paper is not intended to offer a comprehensive review, but offers a representative review of some of the many contributions of USA and North American clinicians to the global scientific dialogue that has guided the development of dental implant therapy.
Tumor necrosis factor inhibitors and acute leukemia in two cases.
Authors: Mehmet Ozen, Onur Keskin, Orhan Kucuksahin, Ufuk Ilgen, Pervin Topcuoglu, Murat Turgay, Murat Toruner, Gunhan Gurman
Journal: Journal of Clinical Oncology (2013)

e18010 Background: Inhibitors of tumor necrosis factor alpha (anti-TNF agents) are commonly used in Crohn’s disease and rheumatoid arthritis. Relationship between TNF inhibitors and development of malignancy, e.g., lymphoma and solid tumors, is defined recently. However, a few authors reported leukemia. Crohn’s disease and also azothioprine may also be associated with leukemia. Here, we are presenting two acute myeloid leukemia (AML) cases using azothioprine and anti-TNF inhibitors for Crohn’s disease. Methods: Observational case report. Results: Case 1: A 56-year-old male patient with active Crohn’s disease for 4 years was refractory to first line mesalazine, corticosteroid and azothioprine treatment. So, anti-TNF monoclonal antibody (moAb) (Adalimumab) had been given. After second dose of adalimumab treatment AML (AML-M2 as FAB) developed. Case 2: A 38-year-old male had been diagnosed with ankylosing spondylitis for 7 years and Crohn’s disease for 2 years. He had been treated with salazopyrin and indomethacin. Anti-TNF etanercept (50 mg/wk) was started 30 months ago due to severe active pulmonary disease. After 1 year, he developed active Crohn’s disease. So, the treatment changed to infliximab. Also, mesalazine and azothioprine were added to treatment. On the 18th month of the infliximab t(15;17) positive acute promyelocytic leukemia were developed in the patient. Conclusions: Blocking TNF with anti TNF agents may cause blocking apoptosis and inhibit natural killer activity. So, antitumoral activity of natural killer cells is blocked by these agents. TNF alpha gene mutation has been associated with CLL, lymphoma, myelodysplastic syndrome and secondary AML. Azothioprine may also increase leukemia, lymphoma and solid tumors risk at patient on anti TNF treatment. Following the diagnosis of Crohn’s disease without immunomodulator treatment a case had developed acute leukemia in the literature. In our patients, anti-TNF, azothioprine and inflammatory bowel disease may be cause acute leukemia cumulatively. Physicians should be careful and regularly check the patients using anti-TNF agents in considering of malignancy development. In conclusion, the pathogenesis of leukemia development after TNF blockage should be clarified.