tbuckley/cabot-search huggingface dataset:
Abstract 1927: High-throughput cell line panel drug screening in organoids and 3D systems
Authors: Tim M. Scales, Anett Rada-Kovacs, Helen N. Pemberton, Ceri M. Wiggins, Nicola J. McCarthy, Annette S. Little, David A. Sorrell
Journal: Cancer Research (2019)

Abstract Cell panel screening of cancer lines grown in standard 2D conditions is a well-established component of the drug discovery toolbox. A sufficiently large cell line panel, reflecting the molecular heterogeneity within a cancer type/sub-type, is required to detect correlations with robust statistical power that aid biomarker identification and patient stratification. However, the heterogenous exposure of tumor cells to nutrients, oxygen and other physical or chemical stresses found in three-dimensional solid tumors also has a role to play in patient response and this is not well mimicked in 2D monolayer cell cultures. To meet the need for high-throughput cell-panel screening in more complex culture systems, we have developed 3D cell-based screens to more closely model the complex physiological environment found in tumors. We have characterised our OncoSignature panel of 300 cell lines for growth as spheroids to produce a 200 strong panel of spheroid forming lines. Using our high-throughput platform to compare drug activity in 2D and 3D cultures, we have identified clear differentials for some compounds in single agent and drug combination screens. For example, MEK and EGFR inhibitors have significantly higher activity in 3D cultures than 2D cultures, with a greater than 10-fold shift in EC50 values. These results were validated in 3D soft agar assays, with similar compound potencies being observed in the HTS spheroid assay and the lower throughput soft-agar assay. We have further extended our 3D screening into organoid cultures. Organoid cultures, with increased complexity in terms of structure and cell heterogeneity compared to spheroids, have historically been challenging to use in high-throughput screening. However, our initial results show encouragingly robust data, with compound activity that is congruent with the genetic characteristics of the organoids. Finally, we used our integrated screening platform to evaluate the power of CRISPR approaches to examine genetic dependencies in KRAS mutant cells in 2D, 3D spheroid and organoid cell cultures. Pooled, next-generation sequencing-linked CRISPRko allows an alternative and complementary genomics approach to arrayed cell panel screening, providing a powerful and robust target identification and validation strategy. Overall, Horizon’s 3D screening platforms will enable large scale interrogation of both drug and gene interactions in more complex cell culture systems. Citation Format: Tim M. Scales, Anett Rada-Kovacs, Helen N. Pemberton, Ceri M. Wiggins, Nicola J. McCarthy, Annette S. Little, David A. Sorrell. High-throughput cell line panel drug screening in organoids and 3D systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1927.
Government
Authors: R. N. Rubin
Journal: JAMA (1989)

As the decade of the 1980s comes to a close, medicine has seen a dramatic shift in the attitude of policymakers—especially the 535 members of Congress. In the post-World War II era when America experienced unbridled optimism, world leadership, and a rapidly growing economy, the focus of legislative leaders in medicine and health was identifying problems and figuring out how best to solve them. If there was a disease that needed treating—a special institute—or at least a research program, was started. If there was an underserved population, a program to get services to those individuals was initiated. The results were spectacular. The National Institutes of Health became the world's focus for outstanding biomedical research, both basic and applied. Most health indicators of the population moved in the right direction, albeit not as fast as some would desire, and were still improving. Access to care was increased, greatly fueled by the
Adverse effects of tracheostomy for sleep apnea
Authors: W. A. Conway
Journal: JAMA (1981)

Tracheostomy resulted in dramatic and sustained improvement in the symptoms of 11 patients with upper airway sleep apnea. However, seven of eight patients who had a standard tracheostomy experienced tracheal granuloma or stomal stenosis. Tracheostomy was revised in five of these eight patients using cervical skin flaps. Three of the 11 patients had a skin flap tracheostomy as the original procedure. Only two of eight patients had tracheal complications after a skin flap procedure. Postoperative problems unrelated to the procedure included recurrent purulent bronchitis in four and psychosocial difficulties in ten. Permanent tracheostomy should be limited to patients with serious cardiopulmonary complications of upper airway sleep apnea. The cervical skin flap is the preferred procedure for long-term tracheostomy in these patients. (<i>JAMA</i>1981;246:347-350)
Use of Plasma Expanders and Physiological Sodium Chloride Solution in Therapy (Dextran, Polyvinylpyrrolidone (PVP), and PVP-I131)
Journal: JAMA (1963)

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
Progress in Cardiovascular Diseases, New York
Journal: JAMA (1967)

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
Racial Differences in Rates of Hepatitis B Virus Infection—United States, 1976-1980
Journal: JAMA (1990)

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
GDNF in treatment of Parkinson's disease: response to editorial
Authors: Anthony E Lang, J William Langston, A Jon Stoessl, Matthew Brodsky, David J Brooks, Vijay Dhawan, William J Elias, Andres M Lozano, Elena Moro, John G Nutt, Mark Stacy, Dennis Turner, G Frederick Wooten
Journal: The Lancet Neurology (2006)
Chronic Effects of Dietary Exposure to Amosite Asbestos and Tremolite in F344 Rats
Authors: Ernest E. McConnell, Henry A. Rutter, Borge M. Ulland, John A. Moore
Journal: Environmental Health Perspectives (1983)

Carcinogenesis bioassays of blocky (nonfibrous) tremolite and amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Fischer 344 rats. The minerals were administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats starting with the dams of the test animals. One group of amosite rats also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250 animals. The offspring from mothers exposed to tremolite or amosite asbestos were smaller at weaning than those from untreated mothers and remained smaller throughout their life. The administration of dimethylhydrazine (DMH) did not affect body weight gain, either in amosite-exposed or nonexposed animals. Survival was comparable in the tremolite and control groups. The amosite-exposed rats showed enhanced survival compared to the untreated controls. DMH exposure reduced survival by approximately one year, although the amosite plus DMH groups survived slightly better than the DMH alone groups. No toxicity or increase in neoplasia was observed in the tremolite-exposed rats compared to the controls. Significant increases (p less than 0.05) in the rates of C-cell carcinomas of the thyroid and monocytic (mononuclear cell) leukemia in male rats were observed in amosite-exposed groups. However, the biological significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and the positive effect was not observed in the amosite plus preweaning gavage group. The biological significance of an increased incidence of mononuclear cell leukemia is questionable, because of a lack of statistical significance in the amosite group when evaluated using life table analysis, lack of significance when compared to the tremolite control group, and the fact that no toxic or neoplastic lesions were observed in the target organs, i.e., gastrointestinal tract and mesothelium. DMH caused a high rate of (62-74%) of intestinal neoplasia in amosite and nonamosite-exposed groups. Neither an enhanced carcinogenic nor protective effect was demonstrated by exposure to amosite asbestos.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Daniel Peter Petrylak, Philip W. Kantoff, Anthony E. Mega, Nicholas J. Vogelzang, Joe Stephenson, Mark T. Fleming, Nancy Stambler, Michaela Petrini, Sara Blattman, Robert Joseph Israel
Journal: Journal of Clinical Oncology (2013)

5018 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized within the cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. A phase 1 dose escalation study of PSMA ADC in taxane-refractory mCRPC has been completed. Methods: Patients with progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1 were eligible. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics, PSA, circulating tumor cells (CTC), immunogenicity and clinical progression were assessed. Serum PSMA ADC and total anti-PSMA ADC antibodies were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Subjects who benefitted from PSMA ADC were eligible for treatment in an extension study. Results: 52 subjects were dosed in 9 dose levels. All subjects received prior docetaxel, 6 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. 16 patients reported peripheral neuropathies, including 3 with grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible elevations in liver function tests (LFTs). Antitumor activity was manifested as reductions either in PSA or in CTCs in approximately 50% of patients at ≥ 1.8 mg/kg PSMA ADC. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. There was no accumulation. Conclusion: PSMA ADC in this study was generally well tolerated in subjects with progressive mCRPC, previously treated with taxane. Antitumor activity was seen at doses ≥ 1.8 mg/kg. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose was determined to be 2.5 mg/kg. A phase 2 trial of PSMA ADC in taxane refractory mCRPC has been initiated at 2.5 mg/kg. Clinical trial information: NCT01414283.
From the Office of the General Counsel. Should physicians treat patients who seek second opinions?
Authors: M. L. Ile
Journal: JAMA (1991)

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
A phase 2 study of cabozantinib in metastatic castrate resistant prostate cancer (mCRPC) with visceral metastases (VM) with very small nuclear circulating tumor cell (vsnCTC) association studies.
Authors: Edwin M. Posadas, Kevin Scher, Jie-Fu Chen, Margarit Sievert, Amy Oppenheim, Nancy P. Moldawer, Beatrice Knudsen, Michael Freeman, Neil Bhowmick, Andre Rogatko, Hsian-Rong Tseng, Leland WK Chung, Robert A. Figlin
Journal: Journal of Clinical Oncology (2016)

e16552 Background: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has recognized clinical activity in mCRPC. While phase 3 studies did not show a significant improvement in overall survival (OS), patients with VM had improved OS compared to those with only osseous metastases in subgroup analysis. Our group has also identified a subgroup of CTCs strongly associated with the presence of VM (Chen, Cancer 2015). We hypothesized that cabozantinib would yield clinical benefit and changes in vsnCTC counts would reflect disease behavior. Methods: This study was designed as an open label study of cabozantinib 60 mg daily, for mCRPC patients with visceral disease. The primary endpoint is clinical benefit rate (radiographic stable disease + partial response (PR) by RECIST 1.1) at 12 weeks (CBR12). Serum PSA concentrations were not used as a primary endpoint. CTCs were enumerated by NanoVelcro CTC Assay and characterized using published methods. Results: Fifteen patients have completed at least 8 weeks of treatment. In this group, 38% had pulmonary metastases; 77% had hepatic metastases; CBR12 was 92% at the time of this report. A quarter of the patients experienced a PR. Mean time to radiographic progression for responders was 38 weeks (19-57). Discordant responses were noted between VM and bone scans. Grade 3 or higher toxicities were compatible with prior studies and observed in 50% of patients. In this advanced mCRPC and relatively heavily pre-treated population, treatment discontinuation due to toxicity was 33%. Eleven of 13 patients were assessable for CTC and imaging. Of the 11 patients, 7 had vsnCTCs detected at baseline. All 7 patients reported subjective improvement that was associated with a decrease in vsnCTCs by 6-8 weeks. In patients who had a PR, no vsnCTCs were detected at 6 weeks while on active treatment. An increase in vsnCTCs was seen prior to visceral progression. Conclusions: Cabozantinib is a TKI with activity in mCRPC with visceral metastases. Toxicity is consistent with previous reports and manageable. The NanoVelcro vsnCTC assay may be informative in these patients. Clinical trial information: NCT01834651.
374. Developing Bone Marrow Transplant and Lentiviral Vectors to Treat Friedreich Ataxia
Authors: Sze Hwee Ong, Dong C. Zhang, Chou H. Sim, Matthew Burton, Dean Phelan, Sarah E.M. Stephenson, Gabrielle R. Wilson, Donald F. Newgreen, Anthony J. Hannan, Paul J. Lockhart, Martin B. Delatycki, Marguerite V. Evans-Galea
Journal: Molecular Therapy (2016)

Friedreich ataxia (FRDA) is a debilitating neurodegenerative disorder with disease onset at around 10-15 years of age. It affects 1 in 29 000 individuals of Caucasian descent and is characterised by progressive gait and limb ataxia. This leads to an ongoing loss of motor coordination which results in affected individuals becoming wheelchair-dependent within 15 years after disease onset - decreasing their quality of life. FRDA patients also experience other disease symptoms such as cardiomyopathy, with heart complications being the leading cause of death with life expectancy decrease to 30-40 years. There is currently no treatment which can cure or slow the neurodegeneration inherent to FRDA and patients undergo various symptomatic treatments to manage disease symptoms. It is thus essential to develop new treatments effective at slowing disease progression to improve the quality of life of FRDA patients. FRDA is caused in most cases by a homozygous GAA trinucleotide repeat expansion within intron 1 of FXN which encodes the frataxin, a mitochondrial protein. As the expansion only reduces the level and does not alter the frataxin protein structure, it is predicted that increasing frataxin will be therapeutically beneficial to FRDA patients. This research aims to introduce frataxin into cells via cell and gene therapy as a potential treatment for FRDA. This introduction of frataxin will not illicit an immune response as patients do produce frataxin at very low levels. We are investigating if transplanting wild-type bone marrow into an irradiated FRDA mouse model increases frataxin and alleviates the neurological phenotype of slight coordination impairment and locomotor defects which develop around six months of age. Reconstitution of the haematopoietic system with GFP-positive donor bone marrow cells in corrected recipient mice indicated successful engraftment following transplant. GFP-positive cells also successfully engrafted into the dorsal root ganglia (DRG) and spinal cord, both major sites of neuropathology in FRDA, of corrected mice - demonstrating low-level chimerism. Immunofluorescence studies showed increased neuronal marking in the DRG of corrected mice, particularly proprioceptive neurons which are highly affected in FRDA patients. Increased frataxin protein is observed in some tissues of corrected mice. Corrected mice also exhibited significant improvement in motor coordination post-transplant. For autologous gene therapy via bone marrow transplant, we are currently developing a lentiviral vector that over-expresses frataxin. These data together illustrate the potential of bone marrow transplant in correcting FRDA in vivo and provide an avenue for the delivery of therapeutic viral vectors for gene therapy.
Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice
Authors: Michael W. Lieberman, Ernest D. Lykissa, Roberto Barrios, Ching Nan Ou, Geeta Kala, Subbarao V. Kala
Journal: Environmental Health Perspectives (1999)

To examine the toxicity of cyclosiloxanes (CSs), the predominant low molecular weight cyclic silicones found in breast implants, we injected female CD-1 mice intraperitoneally with different doses of distillate (3.5-35 g/kg body weight) containing cyclosiloxane D3 (hexamethylcyclotrisiloxane; CS-D3), cyclosiloxane D4 (octamethylcyclotetrasiloxane; CS-D4), cyclosiloxane D5 (decamethylcyclopentasiloxane; CS-D5), and cyclosiloxane D6 (dodecamethylcyclohexasiloxane; CS-D6). The distillate was found to be lethal and all the mice injected with 35 g/kg died within 5-8 days. The median lethal dose (LD50) for distillate was estimated to be approximately 28 g/kg. These mice developed inflammatory lesions of the lung and liver as well as liver cell necrosis with elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and lactic acid dehydrogenase. Administration of CS-D4 alone also produced lethality in these mice with an LD50 of 6-7 g/kg. CS-D4-treated mice also exhibited pulmonary and hepatic lesions and elevated serum enzymes. Analysis of LD50 data indicates that CS-D4 is about as toxic as carbon tetrachloride or trichloroethylene. We measured hydroxyl radical formation in CS-D4-treated mice and found increases of approximately 20-fold in liver and approximately 7-fold in lung on day 4 following injection. Our findings are significant because in vitro experiments have demonstrated that CSs can migrate out of breast implants, and in mouse experiments CSs have been shown to be widely distributed in many organs after a single subcutaneous injection and to persist for at least a year.