tbuckley/cabot-search huggingface dataset:
Abstract 3024: Targeting TMEPAI/PMEPA1 inhibits triple negative breast cancer cell growth and metastasis by enhancing growth suppressive TGF-β signaling
Authors: Prajjal Kanti Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana Saikumar
Journal: Cancer Research (2016)

Abstract Triple negative breast cancers (TNBC) that lack estrogen receptor (ER), progesterone receptor (PR) and hormone epidermal growth factor receptor 2 (HER-2/neu) are aggressive and cause high mortality among breast cancer patients. Transforming growth factor beta (TGF-β) dependency for their aggressive behavior (growth and metastasis) has been well established in many of these tumors. Although targeting TGF-β signaling has major potential to treat TNBCs, however it carries the risk of disturbing the tumor suppressive effects of TGF-β in early tumors and its homeostatic control of normal tissues. Hence there is a need to identify novel targets to impede tumor progression without compromising the beneficial effects of TGF-β signaling. To satisfy this unmet need, earlier we identified that transmembrane prostate androgen induced (TMEPAI/PMEPA1), a direct target gene of TGF-β could act as a “molecular switch” that converts TGF-β from a tumor suppressor to promoter in TNBC. Thus, we undertook the present study that identified a novel compound that blocked TMEPAI expression. We identified terpenoid derivatives (TD) which inhibited the expression of TMEPAI, enhanced TGF-β signaling and blocked proliferation, migration and invasion of several triple negative breast cancer cells in vitro. Our results showed that TD increased phosphorylation of Smad2/3 and increased PTEN, p21 and p27 proteins that cause growth suppression. Concomitantly, TD decreased Akt phosphorylation and reduced Snail and Slug that are required for cell growth and metastasis. Interestingly, TD did not affect the growth of normal human mammary epithelial cells and failed to cause associated molecular changes that can result in growth suppression. Notably, using mice models (nude mice and syngeneic BALB/c mice), we showed that TD reduced tumor burden significantly with little or no toxicity. Consistent with its ability to inhibit Akt phosphorylation and induction of Snail and Slug proteins, TD suppressed lung metastasis of TNBC in mice model. Importantly, reduced tumors derived from TD treated mice exhibited increased expression of pSmad2/3, PTEN, p21, p27 and reduced expression of pAkt compared to tumors obtained from vehicle treated mice. These results suggest that drugs that target TMEPAI will restore homeostatic functions of TGF-β to inhibit growth and metastasis of TNBC and thus prevent new tumor development. Citation Format: Prajjal Kanti Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana Saikumar. Targeting TMEPAI/PMEPA1 inhibits triple negative breast cancer cell growth and metastasis by enhancing growth suppressive TGF-β signaling. [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 3024.
<i>Untitled</i>
Authors: Carrie A. Butt
Journal: JAMA (2016)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Anti-apoptotic Effects of Human Wharton's Jelly-derived Mesenchymal Stem Cells on Skeletal Muscle Cells Mediated via Secretion of XCL1
Authors: SooJin Kwon, Soo Mi Ki, Sang Eon Park, Min-Jeong Kim, Brian Hyung, Na Kyung Lee, Sangmi Shim, Byung-Ok Choi, Duk L Na, Ji Eun Lee, Jong Wook Chang
Journal: Molecular Therapy (2016)

The role of Wharton's jelly-derived human mesenchymal stem cells (WJ-MSCs) in inhibiting muscle cell death has been elucidated in this study. Apoptosis induced by serum deprivation in mouse skeletal myoblast cell lines (C2C12) was significantly reduced when the cell lines were cocultured with WJ-MSCs. Antibody arrays indicated high levels of chemokine (C motif) ligand (XCL1) secretion by cocultured WJ-MSCs and XCL1 protein treatment resulted in complete inhibition of apoptosis in serum-starved C2C12 cells. Apoptosis of C2C12 cells and loss of differentiated C2C12 myotubes induced by lovastatin, another muscle cell death inducer, was also inhibited by XCL1 treatment. However, XCL1 treatment did not inhibit apoptosis of cell lines other than C2C12. When XCL1-siRNA pretreated WJ-MSCs were cocultured with serum-starved C2C12 cells, apoptosis was not inhibited, thus confirming that XCL1 is a key factor in preventing C2C12 cell apoptosis. We demonstrated the therapeutic effect of XCL1 on the zebrafish myopathy model, generated by knock down of a causative gene ADSSL1. Furthermore, the treatment of XCL1 resulted in significant recovery of the zebrafish skeletal muscle defects. These results suggest that human WJ-MSCs and XCL1 protein may act as promising and novel therapeutic agents for treatment of myopathies and other skeletal muscle diseases.
Non-Hodgkin's Lymphomas Associated With Positive Hepatitis-C Virus Infection: A Prospective Multicentric Observational Study On Behalf Of The “Rete Ematologica Lombarda/Hematology Network Of Lombardia Region”
Authors: Sara Rattotti, Luca Arcaini, Virginia Valeria Ferretti, Andrea Rossi, Stefano Fogazzi, Antonino Greco, Luca Baldini, Monica Balzarotti, Pietro Pioltelli, Maurizio Bonfichi, Marzia Varettoni, Manuel Gotti, Lucia Farina, Andrés J.M. Ferreri, Daniele Laszlo, Enrica Morra
Journal: Blood (2013)
Abstract 563: Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity
Authors: Naoto Nishii, Yuta Kondo, Lixin Li, Walter Lau, Hiroyuki Harada, Miyuki Azuma
Journal: Cancer Research (2016)

Abstract [Aim] Toll like receptor (TLRs) are expressed in many types of immune cells and function as a key sensor of microbial products. Ligand binding to TLRs leads to activation of signaling pathways in innate immune cells, particularly dendritic cells and subsequent induction of adaptive immune responses. TLR7/8 agonists have been shown to enhance antiviral and antitumor immune responses via multiple cytokine production such as IFN-α, IL-1β, IL-6 and TNFα. Resiquimod (R-848) is a synthetic imidazoquinoline-like molecule that binds to TLR7 and TLR8. Presently, resiquimod has been used as a topical drug for skin cancer and viral infection, because of severe side effects of systemic administration. Thus far, the clinical results of anti-PD-1 or anti-PD-L1 therapy have showed great benefits by inducing tumor regression and improving survival. However, the patients obtained the benefits of this treatment are around one third. An additional approach is required to enhance the efficacy of PD-1 blockade therapy. In this study, we examined the effects of combined treatment with anti-PD-L1 antibody and a low dose of resiquimod administration in two murine tumor models (a squamous cell carcinoma cell line, SCCVII and a colon carcinoma cell line, Colon26). [Methods] Anti-PD-L1 mAb (MIH5, 200 μg/mouse) and/or resiquimod (1.73 μg/mouse) were intraperitonealy administrated at three times a week and tumor growth was evaluated. [Results and Discussion] In a Colon26 model, either anti-PD-L1 (MIH5) mAb or resiquimod treatment alone slightly decreased tumor growth, but the combined treatment dramatically reduced the tumor growth and completely eradicated the tumor in some of mice. In a SCCVII model, monotherapy with resiquimod markedly reduced the tumor growth and completely eradicated the tumor in some of mice. The combined treatment further enhanced the efficacy. The delayed combined treatment at day 7 also showed the reduction of tumor size. Functional analyses at 3-4 wks after the tumor inoculation revealed that monotherapy with resiquimod in the SCCVII model and the combined treatment in both models significantly enhanced the percentages of IFN-γ+-expressing CD8+ T cells, but did not clearly affect the percentages of Foxp3+ regulatory T cells. Our results suggest that TLR7/8 agonist administration alone markedly enhanced antitumor responses in a selected tumor model and the combined treatment with PD-L1 blockade and a TLR7/8 agonist further amplify their effects. Citation Format: Naoto Nishii, Yuta Kondo, Lixin Li, Walter Lau, Hiroyuki Harada, Miyuki Azuma. Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity. [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 563.
Abstract 712: Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome
Authors: Saara Ollila, Kari Vaahtomeri, Iris Wong, Kaisa Laajanen, Tomi P. Mäkelä.
Journal: Cancer Research (2016)

Abstract Germline mutations in tumor suppressor kinase Lkb1 predispose to Peutz-Jeghers syndrome (PJS), with highly penetrant gastrointestinal polyposis and increased cancer risk. PJS polyps display abnormal growth of both stromal and epithelial cells. We have identified clonally expanding fibroblasts as the drivers of tumorigenesis in PJS mouse models by using Fsp1-Cre and Twist2-Cre mice to restrict Lkb1 deletion to stromal cells (unpublished), highlighting the importance of stromal-epithelial signaling in PJS tumorigenesis. Here, we address the molecular mechanisms of the pathogenesis linked to stromal Lkb1 loss in PJS mouse models. Lkb1 is involved in tissue size control by inhibiting of mTORC1 pathway via AMPK (Shaw et al, Cancer Cell 2004) and by regulating Hippo pathway (Mohseni et al, Nat Cell Biol 2014). First, we investigated the involvement of Lkb1-AMPK-mTORC1 pathway in polyposis. We conditionally deleted both catalytic AMPKá subunits (á1 and á2) in mice using Fsp1-Cre. Surprisingly, Fsp1-Cre-AMPK mice did not develop any tumors by 17 months of age indicating that AMPK is not the critical mediator of Lkb1 tumor suppression in PJS. We next studied the Hippo pathway in polyps of PJS mouse models. Levels of Yap and Taz, the main downstream effectors of Hippo, were elevated in polyps as shown by Western blotting. Immunohistochemical staining revealed profound nuclear Yap/Taz localization indicating transcriptional activity in the stromal compartment throughout the polyps. In contrast, nuclear Yap/Taz staining in epithelial cells was only noted in a restricted polyp base stem cell zone. In addition, we performed RNA-seq analysis of the of Fsp1-Cre;Lkb1flox mouse polyps and noted shared gene expression changes with PJS patient polyps. RNA-seq also revealed significant enrichment of Yap signature, which was validated by qPCR. Finally, we used small intestinal epithelial organoid culture to study the potential of Yap/Taz induced secreted factors to stimulate growth of epithelial cells. We observed that Wnt5a and Epiregulin enhanced epithelial organoid growth, indicating them as candidates mediating the stromal-epithelial signaling and promoting tumorigenesis in PJS polyps. In conclusion, we show that stromal Lkb1 mutations lead to phenotypes identical to germline Lkb1 heterozygosity in mice and propose increased stromal Yap/Taz activity as a potential mechanism to drive PJS tumorigenes. Citation Format: Saara Ollila, Kari Vaahtomeri, Iris Wong, Kaisa Laajanen, Tomi P. Mäkelä. Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome. [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 712.
The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism
Authors: Scott M. Wilhelm, Tracy S. Wang, Daniel T. Ruan, James A. Lee, Sylvia L. Asa, Quan-Yang Duh, Gerard M. Doherty, Miguel F. Herrera, Janice L. Pasieka, Nancy D. Perrier, Shonni J. Silverberg, Carmen C. Solórzano, Cord Sturgeon, Mitchell E. Tublin, Robert Udelsman, Sally E. Carty
Journal: JAMA Surgery (2016)

Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades.To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy.A multidisciplinary panel used PubMed to review the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus.Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise.Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT.
Bringing an Old Drug to a New Treatment Strategy in Treating FLT-ITD AML - Combination of Homoharringtonine and Sorafenib
Authors: Eric S.K. Ho, Stephen Sze Yuen Lam, Cheuk Him Man, Chae Yin Cher, Yok Lam Kwong, Anskar Y.H. Leung
Journal: Blood (2014)
Survival impact of surgical treatment paradigm and perioperative characteristics among patients with stage IIIc epithelial ovarian cancer.
Authors: S. M. Ueda, B. Ajiboye, M. Gerardi, T. Diaz-Montes, R. L. Giuntoli II, R. Bristow
Journal: Journal of Clinical Oncology (2010)

e15506 Background: To assess the clinical and treatment characteristics affecting survival in patients with stage IIIC epithelial ovarian cancer. Methods: All patients undergoing initial treatment for stage IIIC epithelial ovarian cancer at a tertiary referral center between 1/1/95- 12/31/08 were identified. Demographic, surgico-pathologic and treatment variables were abstracted from medical records. Kaplan-Meier and Cox regression were performed to determine factors affecting outcome. Results: 431 ovarian cancer patients met study inclusion criteria. Median age was 59 years; 77.7% of tumors were serous and 81.4% were grade 3. Primary cytoreductive surgery was undertaken in 90.5% of patients, while 9.5% were treated with neoadjuvant chemotherapy. Overall, 70.3% of primary surgery patients were left with optimal (≤ 1 cm) residual disease, and 50.9% had complete cytoreduction to no gross residual disease. Optimal primary cytoreduction was associated with a median overall survival of 60.9 months compared to 32.7 and 30.7 months for suboptimal surgery and neoadjuvant chemotherapy (p < 0.001). Complete cytoreduction, compared to optimal but visible and suboptimal residual disease, was associated with a superior progression free survival (29.9 vs. 16.4 vs. 9.3 months, p < 0.001) and overall survival (79.7 vs. 32.8 vs. 29.6 months, p < 0.001). Adjuvant platinum chemotherapy was associated with improved overall survival (45.2 vs. 24.5 months, p = 0.02), while major surgical morbidity (26.0 vs. 54.8 months, p < 0.001) and serum albumin< 3.5 g/dL (29.8 vs. 54.8 months, p = 0.01) predicted inferior overall survival. On multivariate analysis, tumor grade, residual disease status, adjuvant platinum chemotherapy, major operative morbidity, and serum albumin < 3.5 g/dL were independently predictive of overall survival. Conclusions: Complete cytoreduction to no gross residual disease was associated with the most favorable outcome in Stage IIIC ovarian cancer patients, with a median overall survival approaching 80 months, and should be the standard surgical objective. The survival outcome achievable with neoadjuvant chemotherapy approximated that of suboptimal primary surgery. No significant financial relationships to disclose.
Prognostic effect of hormone receptor status in early HER2-positive breast cancer.
Authors: C. Castaneda Altamirano, H. L. Gomez, V. E. Carlos, W. R. Cruz, R. G. Velarde, M. R. Garces, J. F. Suazo, T. Vidaurre, S. P. Neciosup, C. Vallejos Sologuren
Journal: Journal of Clinical Oncology (2010)

e11074
Stroke Prevention in Atrial Fibrillation Study. Final results.
Authors: Ruth Mcbride
Journal: Circulation (1991)

Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke.The Stroke Prevention in Atrial Fibrillation Study, a multicenter, randomized trial, compared 325 mg/day aspirin (double-blind) or warfarin with placebo for prevention of ischemic stroke and systemic embolism (primary events), and included 1,330 inpatients and outpatients with constant or intermittent atrial fibrillation. During a mean follow-up of 1.3 years, the rate of primary events in patients assigned to placebo was 6.3% per year and was reduced by 42% in those assigned to aspirin (3.6% per year; p = 0.02; 95% confidence interval, 9-63%). In the subgroup of warfarin-eligible patients (most less than 76 years old), warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67% (warfarin versus placebo, 2.3% versus 7.4% per year; p = 0.01; 95% confidence interval, 27-85%). Primary events or death were reduced 58% (p = 0.01) by warfarin and 32% (p = 0.02) by aspirin. The risk of significant bleeding was 1.5%, 1.4%, and 1.6% per year in patients assigned to warfarin, aspirin, and placebo, respectively.Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation. Because warfarin-eligible patients composed a subset of all aspirin-eligible patients, the magnitude of reduction in events by warfarin versus aspirin cannot be compared. Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin, and the trial is continuing to address this issue. Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke.
Abstract 765: The manipulation of FAP expression and its role in SDF-1 and IL-6 secretion by fibroblasts and melanoma cells
Authors: Zachary B. Fisher, Yuko J. Miyamoto
Journal: Cancer Research (2016)

Abstract The cancer microenvironment surrounds tumors and primarily consists of fibroblasts and immune cells that cancer cells utiliaze to support their growth and invasion. Cancer-associated fibroblasts (CAFs) are the most prominent cell type in the microenvironment. They are attracted to tumors and activated by signals from cancer cells, including transforming growth factor-â (TGF-â). Following activation, CAFs display FAP on their surface, which breaks bonds in the extracellular matrix (ECM), creating space for cancer cells to migrate. CAFs also secrete cytokines, including stromal cell-derived factor-1 (SDF-1) and interleukin-6 (IL-6), to initiate this migration. This study seeks to determine if there is a link between the expression of fibroblast activation protein (FAP) and the specific production of SDF-1 and IL-6. Flow cytometry was used to verify the expression of FAP by the Malme-3 fibroblast cell line at an average rate of 50.6% and in the Malme-3M melanoma cell line at 4.8%. TGF-â treatment increased FAP expression in Malme-3M melanoma cells (50% increase), indicating a prominent role in cell transformation. siRNA transfection was also used to reduce FAP expression in both the fibroblasts (48.4% decrease) and the melanoma cells after initial TGF-â activation (11.6% decrease). Preliminary data from intracellular staining and ELISA analysis suggest that SDF-1 and IL-6 production both increased in melanoma cells in direct correlation to FAP expression in, but may be inversely related in fibroblasts. Future studies will further analyze the FAP expression levels and cytokine secretion of both cell types in different microenvironments to elucidate the relationship between FAP expression in cancer and the secretion of SDF-1 and IL-6. Citation Format: Zachary B. Fisher, Yuko J. Miyamoto. The manipulation of FAP expression and its role in SDF-1 and IL-6 secretion by fibroblasts and melanoma 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 765.
Combination of Vorinostat Plus Bortezomib for the Treatment of Patients with Multiple Myeloma Who Have Previously Received Bortezomib
Authors: Donna M. Weber, Sundar Jagannath, Ronald Sobecks, Gary Schiller, Lisa Chiacchierini, David Reiser, Carol Oerth, Jose Garcia-Vargas, Syed Rizvi
Journal: Blood (2008)