tbuckley/cabot-search huggingface dataset:
Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture
Authors: Anne R. Cappola, Dolores M. Shoback
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
Evaluation of anti-cancer stem cell activity of the anti-DLL4 antibody MEDI0639 in a phase I clinical trial of SCLC.
Authors: Haifeng Bao, Xiaoru Chen, Suneetha Thomas, Xiaoqing Shi, Patrick Strout, Elaine Hurt, Song Cho, Patricia A Burke, Mohammed M. Dar
Journal: Journal of Clinical Oncology (2016)

e20093 Background: Small-cell lung cancer (SCLC) is a very aggressive lung cancer with a high metastatic potential. Many patients with SCLC initially respond to standard-of-care therapy but have rapid recurrence. The high metastatic potential and rapid recurrence may be driven by cancer stem cells (CSCs). MEDI0639 is a human monoclonal antibody that selectively binds to DLL4 and inhibits DLL4-Notch receptor signaling. Preclinical studies have demonstrated that DLL4 blockade reduces tumor cell proliferation and cancer stem cell frequency in various tumors. The objective of this study was to evaluate effect of MEDI0639 treatment on CSCs in patients with SCLC. Methods: Nine SCLC patients were enrolled in this phase I single-agent study of MEDI0639. Pre- and post-treatment tumor biopsies were collected at screening and Day 15 of cycle one. CSC frequency and CSC gene expression in tumor samples were analyzed by DepArray and RT-PCR, respectively. Tumor CSC activity was also assessed by an ex vivo sphere formation assay. Circulating tumor cells (CTCs) and circulating CSCs were measured by CellSearch at different time points. Results: The tumor CSC activity was suppressed ( > 30%) after treatment with MEDI0639 in 4 of 8 patients with evaluable tumor biopsy samples. Three of the 8 patients also demonstrated > 50% reductions tumor CSC count after MEDI0639 treatment. Expression levels of CSC genes (CD133, EZH2, and ASCL1) were decreased after MEDI0639 treatment in 3 of 7 patients with adequate tumor RNA samples. In 2 patients, CTC and circulating CSC counts were decreased to 0, concurrent with suppression of CSC gene expression and CSC count or activities in tumor samples, after 1 or 2 cycles of MEDI0639 treatment. Conclusions: Our data suggests that MEDI0639 may suppress CSC counts and activities in a subpopulation of SCLC patients and thus warrants a further study with more patients. Clinical trial information: NCT01577745.
Nanostructured recombinant cytokines: A highly stable alternative to short-lived prophylactics
Authors: Débora Torrealba, David Parra, Joaquin Seras-Franzoso, Eva Vallejos-Vidal, Daniel Yero, Isidre Gibert, Antonio Villaverde, Elena Garcia-Fruitós, Nerea Roher
Journal: Biomaterials (2016)
Isolation of brain cancer stem cells using signaling pathway reporters
Authors: Irving Weissman
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5006 

This study is designed to improve the definition and functional characterization of brain tumor stem cells (BTSC). In some brain tumors, the presence of the normal neural stem cell-associated antigen, CD133, could predict the tumorigenic properties of the cells. However, experiments in our lab have shown that CD133 may not be a universal marker for brain tumor stem cells, and alternative experimental strategies are required. Our working hypothesis is that the activity level of signaling pathways may also be a distinctive hallmark of BTSC. Our methodology involves the fractionation of tumor cells based on biochemical activities associated with self-renewal, and thus provides a functional method that complements the phenotypic method used for cancer stem cell isolation.    Our laboratory has developed a paradigm for the identification of cancer stem cells in human Medulloblastoma (MB) and Glioblastoma Multiformae (GBM): First, a xenograft model for these human brain tumors was established using newborn immunocompromised mice. Injection of fresh, non-fractionated human MB or GBM cells into the cerebellum or lateral ventricles, respectively, has resulted in successful recapitulation of the original tumors. This xenograft model provides the platform by which the tumorigenicity of select tumor cell populations is assessed.    Fractionation of fresh tumor cells from MB and GBM is based on the activity of two signaling pathways associated with self-renewal: the Wnt and Hedgehog (Hh) pathways. The important roles of these pathways in normal progenitor self-renewal, and mutations found in CNS malignancies, suggest that their deregulation may contribute to MB and GBM tumorigenesis. To assess the state of intracellular Hh or Wnt pathway stimulation, specific intracellular reporters were generated, in which GFP reporter gene expression is dependent on pathway-activated transcription. Conserved elements responsive to either Gli or beta-catenin were placed upstream of a GFP gene to report the activity level of the Hh or Wnt pathways, respectively. These cassettes were inserted into Lentiviral vectors, with which we have achieved high efficiency of transdcution into primary human tumor cells.    These specific intracellular reporters for the Wnt and Hedgehog pathways were used to isolate primary human Medulloblastoma cell populations based on the level of activity. The relevance of these signaling pathways to tumor initiation was then tested in in vitro clonogenic assays as well as in vivo tumor transplantation experiments. Future experiments will assess the direct effect of specific pathway inhibitors on the growth of brain tumor stem cells.    The purification of BTSC will be followed by the characterization of mutations, chromosomal aberrations, active signaling pathways and unique surface antigens. This knowledge will guide the development of highly specific and more effective anti-brain cancer therapies.
Regulatory Divergence among Beta-Keratin Genes during Bird Evolution
Authors: Maloyjo Joyraj Bhattacharjee, Chun-Ping Yu, Jinn-Jy Lin, Chen Siang Ng, Tzi-Yuan Wang, Hsin-Hung Lin, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2016)

Feathers, which are mainly composed of aand b-keratins, are highly diversified, largely owing to duplication and diversification of b-keratin genes during bird evolution.However, little is known about the regulatory changes that contributed to the expressional diversification of b-keratin genes.To address this issue, we studied transcriptomes from five different parts of chicken contour and flight feathers.From these transcriptomes we inferred b-keratin enriched coexpression modules of genes and predicted transcription factors (TFs) of b-keratin genes.In total, we predicted 262 TFtarget gene relationships in which 56 TFs regulate 91 b-keratin genes; we validated 14 of them by in vitro tests.A dual criterion of TF enrichment and "TF-target gene" expression correlation identified 26 TFs as the major regulators of bkeratin genes.According to our predictions, the ancestral scale and claw b-keratin genes have common and unique regulators, whereas most feather b-keratin genes show chromosome-wise regulation, distinct from scale and claw bkeratin genes.Thus, after expansion from the b-keratin gene on Chr7 to other chromosomes, which still shares a TF with scale and claw b-keratin genes, most feather b-keratin genes have recruited distinct or chromosome-specific regulators.Moreover, our data showed correlated gene expression profiles, positive or negative, between predicted TFs and their target genes over the five studied feather regions.Therefore, regulatory divergences among feather b-keratin genes have contributed to structural differences among different parts of feathers.Our study sheds light on how feather b-keratin genes have diverged in regulation from scale and claw b-keratin genes and among themselves.
CD301b + Mononuclear Phagocytes Maintain Positive Energy Balance through Secretion of Resistin-like Molecule Alpha
Authors: Yosuke Kumamoto, Joao Paulo G. Camporez, Michael J. Jurczak, Marya Shanabrough, Tamas Horvath, Gerald I. Shulman, Akiko Iwasaki
Journal: Immunity (2016)
AML1/ETO Cooperates with HIF1α to Promote Leukemogenesis through DNMT3a Transactivation
Authors: Xiaoning Gao, Fei Yan, Ji Lin, Li Gao, Xiaolin Lu, Shengcai Wei, Na Shen, Jiuxia Pang, Qiaoyang Ning, Ailing Deng, Yihan Xu, Jinlong Shi, Yonghui Li, Shujun Liu, Li Yu
Journal: Blood (2014)
Prevention of colitis by controlled oral drug delivery of carbon monoxide
Authors: Christoph Steiger, Kazuhiko Uchiyama, Tomohisa Takagi, Katsura Mizushima, Yasuki Higashimura, Marcus Gutmann, Cornelius Hermann, Svetlana Botov, Hans-Günther Schmalz, Yuji Naito, Lorenz Meinel
Journal: Journal of Controlled Release (2016)
Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1
Authors: Philip J Mease, Désirée van der Heijde, Christopher T Ritchlin, Masato Okada, Raquel S Cuchacovich, Catherine L Shuler, Chen-Yen Lin, Daniel K Braun, Chin H Lee, Dafna D Gladman
Journal: Annals of the Rheumatic Diseases (2016)

To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA).Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24.Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05).In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo.NCT01695239; EudraCT2011-002326-49; Results.
Kaposi's Sarcoma, Vascular Permeability, and Scientific Integrity
Authors: Syed Zaki Salahuddin
Journal: JAMA (1994)

<h3>To the Editor.</h3> —We are writing to you in response to the Brief Report by Dr M. Witte and colleagues.<sup>1</sup>We regret not getting a chance to address the issues raised in the report before publication and strongly object to the public assertion that implied some form of scientific impropriety. The customary scientific forum was used and our response to the critique by Witte et al was subjected to peer review by<i>Science</i>in 1992; however, the exchange was not considered worthy of publication by the reviewers for<i>Science</i>. Nevertheless, we made a concerted effort to address the concerns of Witte et al at the laboratory level. Dr C. Witte was contacted and we offered to have Dr Sakurada visit his laboratory and do experiments there, to have C. Witte visit our laboratory, or to send our cells and protocols to him. Our offer was flatly rejected. The same
Effects of tamoxifen and imatinib on the radiosensitivity of breast carcinoma cells
Authors: C. Mundhenke, P. Niehoff, K. Weber, M. Weigel, D. O. Bauerschlag, C. Schem, M. Bauer, W. Jonat, N. Maass
Journal: Journal of Clinical Oncology (2008)

14639 Background: Radiotherapy is commonly used in different stages of breast cancer. It is able to effect intracellular signal transduction leading to inhibition of cell proliferation. Impact of targeted agents on radiosensitivity is partially unknown. The selective estrogen receptor modulator Tamoxifen was the first targeted drug available to treat hormone receptor positive breast cancer. Tyrosine kinase inhibitors are a new family of targeted drugs for cancer treatment. One of them is Imatinib mesylate, a selective inhibitor of bcr-abl, PRGFR α and β and c-kit. First developed to cure chronic myeloid leukaemia it has now shown its anti-proliferative effects in a range of solid cancers. This study evaluates whether Tamoxifen or Imatinib have an influence on radiosensitivity in breast cancer cell lines. Methods: Colony-forming tests of MCF 7 (hormone-receptor positive) and MDA MB 231 (negative) were used to study differences in cell proliferation under incubation with Tamoxifen, Imatinib and radiation. Changes in expression and phosphorylation of target receptors were detected using western blot. Results: Tamoxifen sensitizes hormone receptor positive MCF 7 cells for irradiation while MDA MB 231 cells show no significant difference in cell growth. An increase of EGF-receptor expression could be detected in both cell lines. Estrogen-receptor α expression decreased in MCF-7. Independent of hormone receptor status, the combination of Imatinib and radiotherapy showed a significantly enhanced inhibition of cell proliferation in both cell lines compared to radiotherapy alone. Differences in PDGFR expression could not be detected but receptor phosphorylation was significantly inhibited when treated with Imatinib. Conclusions: Tamoxifen enhances anti- proliferative effects on hormone receptor positive cells caused by radiotherapy due to changes in EGFR and estrogen-receptor expression. Imatinib treatment combined with radiotherapy leads in both cell lines to a significant benefit which might be influenced through inhibition of PDGFR phosphorylation. Imatinib could function as a radio sensitizer in breast cancer patients undergoing radiotherapy. Further in vivo studies are needed to evaluate the benefit of Imatinib in combination with radiotherapy in the clinical setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Companion and complementary diagnostics for PD-L1 expression assessment in non-small cell lung cancer.
Authors: Steven M. Anderson, Bruce Horten, Bryan McCune, Ronald Paler
Journal: Journal of Clinical Oncology (2016)

11612 Background: Recently two different immunohistochemical assays for PD-L1 expression in non-small cell lung cancers have been approved in conjunction with immune checkpoint inhibitors. One assay using the rabbit anti-PD-L1 clone 22C3 on the Dako platform, is a companion diagnostic for Pembrolizumab. The second assay using the rabbit anti-PD-L1 clone 28-8 on the Dako platform is a complementary diagnostic for Nivlolumab. A companion diagnostic is defined as a test that is necessary for the safe and efficacious use of a specific therapy and a complementary diagnostic is defined as a test providing additional information about how a drug is used for patient management. Because the assays rely on different procedures and have different intended uses, our laboratory network has provided both formats. Methods: We evaluated the trends in utilization of the two assays and the analytical performance features of the assays post-approval. Results: A greater number tests have been ordered since approval for the assay associated with the potential use of Pembrolizumab versus Nivolumab. This may be in part due to the differences in labeling and intended use of the assays. The two formats were evaluated for the percentage of samples considered positive for PD-L1 staining, spectrum of staining results and percentage of samples that are not evaluable for PD-L1 expression. Results with the 22C3 antibody demonstrated staining ( > 1%) in 55.6% of the samples, with 28% of the samples showing high PD-L1 expression ( > 50% of the tumor staining positive). Approximately 20% of the samples were not evaluable, mainly because of insufficient tumor cells ( < 100). Staining results with the 28-8 antibody, demonstrated positive tumor cell staining ( > 1%) in 46.9% of the tested samples, and 16% of the samples submitted for testing could not be evaluated, because of the lack of sufficient tumor cells. Conclusions: The results of this analysis show that both companion and complementary diagnostic assays are being used for patient management in non-small cell lung cancer. While the companion diagnostic assay in this initial assessment seems to have greater utilization among clinicians, both assays show expected analytical performance characteristics.
Outbreak investigation for toxigenic Corynebacterium diphtheriae wound infections in refugees from Northeast Africa and Syria in Switzerland and Germany by whole genome sequencing
Authors: D.M. Meinel, R. Kuehl, R. Zbinden, V. Boskova, C. Garzoni, D. Fadini, M. Dolina, B. Blümel, T. Weibel, S. Tschudin-Sutter, A.F. Widmer, J.A. Bielicki, A. Dierig, U. Heininger, R. Konrad, A. Berger, V. Hinic, D. Goldenberger, A. Blaich, T. Stadler, M. Battegay, A. Sing, A. Egli
Journal: Clinical Microbiology and Infection (2016)

Toxigenic Corynebacterium diphtheriae is an important and potentially fatal threat to patients and public health. During the current dramatic influx of refugees into Europe, our objective was to use whole genome sequencing for the characterization of a suspected outbreak of C. diphtheriae wound infections among refugees. After conventional culture, we identified C. diphtheriae using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and investigated toxigenicity by PCR. Whole genome sequencing was performed on a MiSeq Illumina with >70×coverage, 2×250 bp read length, and mapping against a reference genome. Twenty cases of cutaneous C. diphtheriae in refugees from East African countries and Syria identified between April and August 2015 were included. Patients presented with wound infections shortly after arrival in Switzerland and Germany. Toxin production was detected in 9/20 (45%) isolates. Whole genome sequencing-based typing revealed relatedness between isolates using neighbour-joining algorithms. We detected three separate clusters among epidemiologically related refugees. Although the isolates within a cluster showed strong relatedness, isolates differed by >50 nucleotide polymorphisms. Toxigenic C. diphtheriae associated wound infections are currently observed more frequently in Europe, due to refugees travelling under poor hygienic conditions. Close genetic relatedness of C. diphtheriae isolates from 20 refugees with wound infections indicates likely transmission between patients. However, the diversity within each cluster and phylogenetic time-tree analysis suggest that transmissions happened several months ago, most likely outside Europe. Whole genome sequencing offers the potential to describe outbreaks at very high resolution and is a helpful tool in infection tracking and identification of transmission routes.
Discordances Between Pre-Natal and Post-Natal Diagnoses of Congenital Heart Diseases and Impact on Care Strategies
Authors: Myriam Bensemlali, Julien Stirnemann, Jérôme Le Bidois, Marilyne Lévy, Francesca Raimondi, Eric Hery, Bertrand Stos, Bettina Bessières, Younes Boudjemline, Damien Bonnet
Journal: Journal of the American College of Cardiology (2016)
Case 19-1968
Authors: Gerald Klatskin, Benjamin Castleman
Journal: New England Journal of Medicine (1968)

PRESENTATION OF CASE First admission. A seventy-seven-year-old man was admitted to the hospital because of epigastric pain and jaundice.For many years he had experienced indigestion after eating fried food. He had never been jaundiced or received a blood transfusion. Two days before entry epigastric pain developed suddenly, without nausea or vomiting, and on the next day he noticed that the urine was dark.The patient was mildly icteric. The edge of the liver, which was very tender, was palpable 2 fingerbreadths below the right costal margin; no masses were felt in the abdomen.The temperature was 99°F, the . . .
Patterns of genic intolerance of rare copy number variation in 59,898 human exomes
Authors: Douglas M Ruderfer, Tymor Hamamsy, Monkol Lek, Konrad J Karczewski, David Kavanagh, Kaitlin E Samocha, Mark J Daly, Daniel G MacArthur, Menachem Fromer, Shaun M Purcell
Journal: Nature Genetics (2016)