tbuckley/cabot-search huggingface dataset:
The development of tumor-activated hyaluronic acid chemotherapeutic drugs
Authors: Tracey Brown, Kaushaliya Vaghela, Jeanette Falzon, Michelle Paul, Peter Gibbs, Richard Fox, Gary Brownlee
Journal: Cancer Research (2007)

4721  Introduction: The non-selective nature of chemotherapeutic drugs necessitates the administration of high doses to achieve therapeutic levels within the tumor, often resulting in severe side-effects. An approach to increasing efficacy while alleviating treatment toxicity has been to design pro-drugs that are enzymically activated within the tumor. In many tumors β-glucuronidase (s-GLUC) is present at higher levels than in the surrounding normal tissue. In contrast to normal tissue, tumoral s-GLUC is in part localized extracellularly, primarily due to secretion by inflammatory cells and disintegrating tumor cells. Improved therapeutic responses have been observed with several anticancer drugs conjugated to glucuronic acid with the limitation of cellular uptake and penetration. Proprietary formulations containing the polysaccharide, hyaluronic acid (HA) utilise the unique physiochemical and biological properties of HA enabling it to function as an excipient imparting its own pharmacological activity through directing the entrained anticancer agent/s to over-expressed CD44 receptors. Once localized in the tumor, the HA/drug complex aggregates forming a drug depot, increasing drug retention at the site; subsequently efficacy is enhanced through increased co-internalisation of the drug and HA. Preliminary pre-clinical studies demonstrated that high molecular weight HA up-regulated intra-tumoral s-GLUC; which could potentially exert a beneficial effect on glucuronide pro-drugs. The purpose of this study was to determine the mechanism and potential therapeutic effect of HA-mediated intra-tumoral activation of glucuronide pro-drugs.  Methodology: The effect of a HA formulation of irinotecan (HyCAMP) on the genetic and cellular activation of tumoral s-GLUC was established in eight colon cancer cell lines treated with varying concentrations of HyCAMP, HA or irinotecan. After treatment the s-GLUC gene was quantitated using real time PCR and protein activity using a colorimetric assay. In vivo, [3H]irinotecan formulated as Camptosar® or HyCAMP was intravenously administered to nude mice bearing human colon cancer xenografts. At 5min - 96hr after drug administration, all body organs and fluids were collected and quantitatively analysed for irinotecan, SN-38 and SN-38G.  Results: The HA component of the HyCAMP formulation up-regulated both the transcription and translation of tumoral s-GLUC when compared to irinotecan only. In vivo, HyCAMPincreased the intra-tumoral conversion of SN-38G to SN-38 thereby increasing treatment efficacy.  Conclusions: HA formulated drugs enhance the intra-tumoral expression and activity of s-GLUC where the further development of HA anti-cancer agents could result in a new generation of tumor-activated glucuronide pro-drugs which demonstrate superior therapeutic indices as the HA directs the drug to the malignant site while increasing drug activation within the tumor.
Regulation of tumor cell invasion and metastasis by COX-2 and RhoA
Authors: Yu-Wen Chang, Jerry Marlin, Rolf Jakobi
Journal: Cancer Research (2007)

3933  Cyclooxygenase-2 (COX-2) represents an important target for treatment and prevention of colorectal cancer. Although COX-2 signaling is implicated in promoting tumor cell growth and invasion, the molecular mechanisms that mediate these processes are largely unknown. In this study, we show that the RhoA pathway mediates COX-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Disruption of adherens junctions promotes tumor cell invasion and metastasis and is often associated with tumor progression. We detected high levels of RhoA activity in HCA-7 colon carcinoma cells that constitutively express COX-2. Inhibition of COX-2 significantly reduced the levels of RhoA activity in HCA-7 cells, suggesting that constitutive expression of COX-2 stimulates RhoA activity. Interestingly, inhibition of COX-2 or silencing of COX-2 expression with small interfering RNA (siRNA) stimulated the formation of adherens junctions, concomitant with increased protein levels of E-cadherin and α-catenin. Furthermore, inhibition of RhoA or silencing of RhoA expression with siRNA increased the levels of E-cadherin and α-catenin. Inhibition of Rho kinases (ROCKs), the RhoA effector proteins, also increased levels of E-cadherin and α-catenin and stimulated formation of adherens junctions. The motility of HCA-7 cells was significantly decreased when COX-2 or RhoA was inhibited. Therefore, our data reveal a novel molecular mechanism that links COX-2 signaling to disrupt the formation of adherens junctions; COX-2 stimulates the RhoA/ROCK pathway which reduces levels of E-cadherin and α-catenin leading to disruption of adherens junction formation and increased motility. Understanding of COX-2 downstream signaling pathways that promote tumor progression is crucial for the development of novel therapeutic strategies.
Large scale profiling of phospho-proteins in cell and tissue microarrays using phospho specific antibodies: Identification of biomarkers and pharmacodynamic activity for a c-Kit inhibitor
Authors: Herbert Haack, Laura C. Sullivan, Andrew Garton, John D. Haley, Bradley L. Smith
Journal: Cancer Research (2005)

3108  The successful development and use of targeted therapeutics may be improved by the use of biomarkers to characterize drug biological activity and allow patient selection. OSI-930, a small molecule inhibitor of Kit and KDR kinases, has shown growth inhibitory and pro-apoptotic effects in mast cell and SCLC lines in vitro and shows tumor growth inhibitory activity in corresponding xenograft models in vivo. We have used model cell lines and xenografts in large-scale tissue microarray screens with phospho-specific antibodies to identify potential biomarkers for the c-Kit inhibitor and other drug candidates. Cells in culture and xenografts were exposed to the compound and then fixed, embedded and arrayed for IHC analysis. Over 130 phospho-specific and total antibodies were systematically validated for IHC before use on the test samples. The screens successfully identified multiple markers whose expression or phosphorylation was altered by the drug treatment. Specific profiles of expression and inhibition by the compound were observed for mutant and wild-type c-Kit in cell lines. Many of the known downstream targets of c-Kit were identified along with novel markers that have not been previously linked to the drug target. The profile observed for mutant c-Kit using IHC corresponds well with the drug response profile obtained using multi-dimensional LC-MS/MS. In addition, specific tumor and stromal activities of the compound were identified in xenograft arrays, demonstrating the advantage of cellular resolution that can be achieved using tissue microarray profiling. These markers may now be moved forward into validation studies using patient material to determine their clinical usefulness.
Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity
Authors: Zhida Liu, Chuanhui Han, Chunbo Dong, Aijun Shen, Eric Hsu, Zhenhua Ren, Changzheng Lu, Longchao Liu, Anli Zhang, Casey Timmerman, Yang Pu, Yang Wang, Mingyi Chen, Jian Qiao, Yang-Xin Fu
Journal: Science Immunology (2019)

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.
‘Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients’
Authors: Maya H Buch, Andrew Melville, Dennis G McGonagle
Journal: Annals of the Rheumatic Diseases (2019)

Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients' by Humby et al.
Accurate Tracking of the Mutational Landscape of Diploid Hybrid Genomes
Authors: Lorenzo Tattini, Nicolò Tellini, Simone Mozzachiodi, Melania D’Angiolo, Sophie Loeillet, Alain Nicolas, Gianni Liti
Journal: Molecular Biology and Evolution (2019)

Mutations, recombinations, and genome duplications may promote genetic diversity and trigger evolutionary processes. However, quantifying these events in diploid hybrid genomes is challenging. Here, we present an integrated experimental and computational workflow to accurately track the mutational landscape of yeast diploid hybrids (MuLoYDH) in terms of single-nucleotide variants, small insertions/deletions, copy-number variants, aneuploidies, and loss-of-heterozygosity. Pairs of haploid Saccharomyces parents were combined to generate ancestor hybrids with phased genomes and varying levels of heterozygosity. These diploids were evolved under different laboratory protocols, in particular mutation accumulation experiments. Variant simulations enabled the efficient integration of competitive and standard mapping of short reads, depending on local levels of heterozygosity. Experimental validations proved the high accuracy and resolution of our computational approach. Finally, applying MuLoYDH to four different diploids revealed striking genetic background effects. Homozygous Saccharomyces cerevisiae showed a ∼4-fold higher mutation rate compared with its closely related species S. paradoxus. Intraspecies hybrids unveiled that a substantial fraction of the genome (∼250 bp per generation) was shaped by loss-of-heterozygosity, a process strongly inhibited in interspecies hybrids by high levels of sequence divergence between homologous chromosomes. In contrast, interspecies hybrids exhibited higher single-nucleotide mutation rates compared with intraspecies hybrids. MuLoYDH provided an unprecedented quantitative insight into the evolutionary processes that mold diploid yeast genomes and can be generalized to other genetic systems.
The Synthesis and Biological Function of a Novel Sandwich‐Type Complex Based on {SbW<sub>9</sub>} and Flexible bpp Ligand
Authors: Lu Wang, Shubin Li, Yu Kai, Jiang Zhu, Huijie Shi, Baibin Zhou, Jiaren Liu
Journal: Advanced Healthcare Materials (2019)

Abstract A novel sandwich‐type complex [Na(H 2 O) 4 ][{Na 3 (H 2 O) 5 }{Mn 3 (bpp) 3 } (SbW 9 O 33 ) 2 }]·8H 3 O (MnSbW‐bpp) (bpp = 1,3‐bis(4‐pyridyl) propane) is synthesized and characterized by elemental analysis, IR, thermogravimetric analysis, and single‐crystal X‐ray diffraction. The MnSbW‐bpp compound is the first sandwich case bridged by a flexible ligand. Its biological function of MnSbW‐bpp in antitumor activity is also determined in vitro and in vivo. The inhibitory proliferation and induction of apoptosis are performed by flow cytometry assay, S180 (sarcoma) tumor xenograft in ICR mice, the color Doppler ultrasound monitor, and TdT‐mediated dUTP‐biotin nick end labeling assay. The results show that the novel compound—MnSbW‐bpp—is synthesized and identified by its physical and chemical characteristics, such as the fluorescent and paramagnetic activities. MnSbW‐bpp indicates a potency inhibition of human cancer lines, such as SGC‐7901, HT‐29, HepG2, Hela, U2OS, SaoS2, and HMC cells. MnSbW‐bpp also inhibits the growth of tumor xenograft in mice, induced cell apoptosis, and released cytochrome c in vivo and in vitro. Thus, MnSbW‐bpp, as a new compound, possesses the potent inhibition of cancer cells, which indicates that the MnSbW‐bpp has potential merit for the further evaluation of a novel antitumor agent.
Biofilm as a risk factor in implant treatment
Authors: Diane M. Daubert, Bradley F. Weinstein
Journal: Periodontology 2000 (2019)

Abstract This article summarizes the microbiological findings at dental implants, drawing distinctions between the peri‐implant microbiome and the periodontal microbiome, and summarizes what is known regarding biofilm as a risk factor for specific stages of implant treatment. Targeted microbial analysis is reviewed as well as the latest results from open‐ended sequencing of the peri‐implant flora. At this time there remains a lack of consensus for a specific microbial profile that is associated with peri‐implantitis, suggesting that there may be other factors which influence the microbiome such as titanium surface dissolution. Therapeutic interventions to address the biofilm are presented at the preoperative, perioperative, and postoperative stages. Evidence supports that perioperative chlorhexidine reduces biofilm‐related implant complications and failure. Regular maintenance for dental implants is also shown to reduce peri‐implant mucositis and implant failure. Maintenance procedures should aim to disrupt the biofilm without damaging the titanium dioxide surface layer in an effort to prevent further oxidation. Evidence supports the use of glycine powder air polishing as a valuable adjunct to conventional therapies for use at implant maintenance visits. For the treatment of peri‐implantitis, nonsurgical therapy has not been shown to be effective, and while surgical intervention is not always predictable, it has been shown to be superior to nonsurgical treatment for decontamination of the implant surface that is not covered by bone.
Blood Pressure, Brain Volume and White Matter Hyperintensities, and Dementia Risk
Authors: Shyam Prabhakaran
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
Slow, tight binding inhibition of Hsp90 isoforms correlates with potent anti-proliferative activity in cancer cell lines
Authors: Jeffrey Partridge, Amy Barabasz, Tom Barta, Patrick Fadden, Briana Foley, Tiffany Freed, Phillip Hughes, Steven Hall, Mei Hu, He Huang, Wei Ma, Andy Ommen, John Rice, Anisa Scott, Melanie Silinski, Emlie Smith, Paul Steed, James Veal, Angela Woodward
Journal: Cancer Research (2008)

3943  As the molecular chaperone Hsp90 has emerged as a promising therapeutic target for the treatment of cancer, attention has increasingly focused on the biochemical mechanism of its inhibition. Most of this attention has focused on the apparent inconsistency between the low micromolar in vitro Hsp90 binding potency of geldanamycin and its analogs compared to their low nanomolar activity against cultured cancer cells. Many hypotheses have been put forward to explain this inconsistency including differences between purified and complexed Hsp90, differences in affinity between normal and tumor Hsp90, reduction of the analogs to their dihydroquinones, differential activity against the 4 Hsp90 family members and unique kinetics of Hsp90 inhibition. We present here further evidence of a time dependent shift in affinity for several ATP competitive Hsp90 inhibitors. This time-dependent shift in affinity correlates with the anti-proliferative activity of these compounds against cancer cell lines. In particular, we describe the development of a proteomics-based assay that profiles the ability of compounds to competitively bind to the ATP pocket of all Hsp90 isoforms in a time-dependent manner, the first reported assay for all Hsp90’s. This assay was applied to geldanamycin analogs, radicicol analogs, purine analogs and several of Serenex’s novel Hsp90 inhibitors. While geldanamycins and the Serenex inhibitors exhibit profound time-dependent binding, other classes of Hsp90 inhibitors do not. In fact, geldanamycin and SNX-2112 show an 11-fold and 14-fold increase in potency respectively when drug incubation time is increased from 5 minutes to 1.5 hours. In addition, analysis of the extensive SAR set of Serenex small molecule Hsp90 inhibitors as well as geldanamycin and its analogs reveal that the kinetics of binding can discriminate between Hsp90 family members and thereby create selectivity within the Hsp90 axis. This assay has enabled the identification of compounds with optimal selectivity and binding kinetics and demonstrates that these kinetics correlate with increased anti-proliferative potency against cancer cell lines. Indeed, unlike geldanamycin and its analogs, the Serenex clinical molecule, SNX-2112, is highly potent against the alpha and beta isoforms of Hsp90 but lacks significant activity against the others, Grp94 and Trap1. A model for the modulation of binding kinetics based on x-ray co-crystal data is presented.
Congenital Anomalies in Offspring of Maternal Glucokinase–Maturity-Onset Diabetes of the Young: A Case Report
Authors: Victoria L. Rudland, Jason Pinner, Glynis P. Ross
Journal: Diabetes Care (2019)

A 24-year-old white European woman with diet-treated diabetes since 15 years of age presented prior to her first pregnancy. Her prepregnancy HbA1c was 5.8% (40 mmol/mol), and HbA1c at 12 weeks’ gestation was 6.0% (42 mmol/mol). She received insulin therapy from 13 weeks (up to 0.3 units/kg/day) and had a vaginal delivery of a boy weighing 3,205 g (84th centile) at 37 weeks. He had neonatal jaundice and bilateral vesicoureteral reflux requiring reimplantation surgery (Table 1).

View this table:

Table 1 
Details of GCK-MODY pregnancies in this case report



Her second pregnancy was managed similarly, with insulin therapy from 4 weeks’ gestation (up to 0.7 units/kg/day). The HbA1c was 5.5% (37 mmol/mol) at 8 weeks. She had a vaginal delivery of a healthy girl weighing 3,235 g (33rd centile) following induction of labor at 40 weeks.

Postpartum, the mother’s persistent fasting hyperglycemia, small increment on a 75-g oral glucose tolerance test (6.2, 7.7, and 6.3 mmol/L [fasting, 1 h, and 2 h, respectively]), and two-generation family history of diabetes suggested glucokinase–maturity-onset diabetes of the young (GCK-MODY), which was confirmed on genetic testing (heterozygous glucokinase ( GCK ) mutation c.952G>A, p.Gly318Arg).

Her third pregnancy …
Candidate treatments of brain metastases suggested from<i>in silico</i> gene expression analysis of archival primary breast tumor tissue and brain metastases (BM)
Authors: T. Iyengar, N. L. Tran, B. A. Armstrong, M. E. Berens
Journal: Journal of Clinical Oncology (2009)

e22203 Background: Patients with metastatic breast cancer are living longer due to advances in therapy. Interestingly, there are times when systemic disease is well controlled but progression continues within the central nervous system (CNS). We report our retrospective analysis of gene expression data from the GEO database. Methods: We interrogated the NCBI/GEO database using the following search terms: breast cancer, gene expression, and brain metastases. We identified a set of tissue samples and compared gene expression arrays from 4 separate BM specimens to 7 primary breast cancer specimens; all specimens were Her-2 neu +/ER - tumors except one (information unavailable). Using a t-test, a two-fold or greater change in gene expression was considered significant if the p-value was &lt;0.05. Results: Analysis of the gene expression profiles revealed several gene candidates over expressed in the BM specimens as compared to primary tumor specimens. Of interest are the motility-associated genes (ICAM1, cortactin, DOCK11, and myosin; p&lt;0.03), pro-survival gene (AKT3; p&lt;0.03), the FGF-growth factor signaling pathway (FGF1; p&lt;0.02), and genes positively regulating the epithelial-to-mesenchymal transformation (EMT) process [TGFB1, SNAI2 (SLUG), NOTCH2; p&lt;0.03]. Notably, the TGFB/Slug pathway is influenced by Sonic hedgehog (SHH). SHH inhibitors are currently being investigated in phase I clinical trials. Conclusions: To the best of our knowledge, this is the first analysis to suggest a role for TGFB and SHH signaling as it relates to the metastatic potential of breast cancer. Our findings argue for gene expression analysis on a larger number of BM specimens for discovery and validation of gene candidates important for this malignant progression. As there are drugs already available to target these pathways, the goal would be to accrue more patients with primary or secondary CNS malignancies to assess response. No significant financial relationships to disclose.