tbuckley/cabot-search huggingface dataset:
Abstract 1106: Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2
Authors: Harri Jarvelainen, Gregory P. Botta, Tatiana Hurtado De Mendoza, Erkki Ruoslahti
Journal: Cancer Research (2019)

Abstract Background: Recombinant IL-2 at high doses is an effective immunotherapy treatment for various types of solid tumors. However, its clinical utility has been limited by serious mechanism-based side-effects. The clinical-stage iRGD peptide specifically targets tumors and, via activation of the ‘CendR’ trans-tissue transport pathway, increases tumor penetration and accumulation of various types of co-administered drugs. By selectively increasing the drug delivery into tumors, but not to normal tissues, iRGD potentiates the pharmacological activity of various anti-cancer agents within tumor tissue, while reducing their toxicities. In this study we investigate whether co-administration of iRGD with low-dose IL-2 can improve the tumor immune microenvironment by increasing in the ratios of tumor-killing effector CD8 cells vs. the immunosuppressive T-regulatory cells. Methods: Subcutaneous breast tumors (4T1) were generated in immunocompetent mice. Mice were treated with either vehicle control, iRGD, IL-2, or IL-2 + iRGD for 5 days. Tumors were preserved for immunohistochemistry (IHC) or enzymatically digested for fluorescence activated cell sorting (FACS) 16 hours after the last dosing. The FACS and IHC panels were designed to detect the percentage of total T cells, CD4 and CD8 T cells, and Treg cells. Results: Low doses of IL-2 alone were found to increase Tregs within the tumor but had no effect in CD4 or CD8 effector T cells, compared to vehicle treatment. However, when Low dose IL-2 was co-administered with iRGD, we observed a significantly lower percentage of T regs and an increase in CD4 effector T cells. More importantly the ratio of CD8 / Treg cells was increased by at least 10-fold, compared to low dose IL-2 alone. Conclusions: The combination treatment with iRGD and low doses of IL-2 is capable of favorably altering the tumor immune microenvironment such that immunosuppressive T reg cells were reduced, while there was an increase in the effector CD4 and CD8 T-cell populations. The tumor-selective IL-2 pharmacology benefit obtained with iRGD co-administration may provide new options for the use of the well-validated IL-2 in solid tumor patients, including a strategy to overcome the primary resistance to PD-1 blockade. Citation Format: Harri Jarvelainen, Gregory P. Botta, Tatiana Hurtado De Mendoza, Erkki Ruoslahti. Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2 [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 1106.
Abstract 1458: Study on cervical cancer preventive effect of HPV vaccine in Japan
Authors: Masato Nishimura, Tomohiro Kagawa, Ayuka Mineda, Eri Takiguchi, Akiko Abe, Minoru Irahara
Journal: Cancer Research (2019)

Abstract Objective: In Japan, side effects are emphasized and ingestion of HPV vaccine is not widespread. Meanwhile, the number of people suffering from cervical cancer has increased, and there is concern that deaths due to cervical cancer will increase. The objective of this study is to clarify the differences in the frequency of cytological abnormalities by presence or absence of HPV vaccination, sex hormone intake, and smoking history. Methods: We examined each item described in medical questionnaire of a consultant who received cervical cancer screening in April 2015 - March 2016 and cytological diagnosis. Results: There are 23,001 consultation examiners for 1 year. Of these, 3609 people aged 20-29, 6457 people aged 30-39 years old, 4433 people aged 40-49 years old were examined each item. With or without HPV vaccination, the frequency of cytological abnormalities (ASC-US and more) in 20-29 years old was 8/262 (3.1%), 121/3307 (3.7%), and there was no difference. Frequency of LSIL or more was significantly lower in vaccinates as 0/262 (0%) vs 70/3307 (2.3%) p&amp;lt;0.05. There was no difference in the frequency of cytological abnormalities between the groups at 30-39 years old and 40-49 years old. With regard to the presence or absence of sex hormones, there was no difference in the frequency of cytological abnormalities in all ages. With smoking history, the frequency of LSIL or more was significantly higher in a group with smoking history, at the ages of 20-29 years (3.7% vs 1.4%) and 30-39 years (2.3% vs 1.2%). Conclusion: If there is smoking history, it is important to undergo regular cervical cancer screening. In addition, HPV vaccination reduces the frequency of cytological abnormalities, so HPV vaccine is also important for the prevention of cervical cancer. Citation Format: Masato Nishimura, Tomohiro Kagawa, Ayuka Mineda, Eri Takiguchi, Akiko Abe, Minoru Irahara. Study on cervical cancer preventive effect of HPV vaccine in Japan [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 1458.
Branched neurotensin for selective tumor tracing and therapy
Authors: Luisa Bracci, Chiara Falciani, Alessandro Pini, Monica Fabbrini, Barbara Lelli, Silvia Pileri, Jlenia Brunetti, Luisa Lozzi, Stefano Bindi, Silvia Scali
Journal: Cancer Research (2007)

3982   The finding that receptors for different endogenous regulatory peptides, like the neuropeptide neurotensin (NT), are over-expressed in different human cancers, has opened new perspectives on the use of synthetic peptides for tumor-selective targeting (1). Peptide ligands carrying cytotoxic moieties or radiotracers might act as drugs or diagnostics. Nonetheless, the use of peptides as drugs has largely been limited by their short half-life. Peptides are physiologically hydrolysed by proteases and peptidases and the chemical modifications necessary to stabilize endogenous sequence can deeply modify peptide affinity and specificity.  We demonstrated that NT, like several other endogenous peptides, retains its biological activity and becomes resistant to proteolysis when synthesized in a branched form (2).  NT receptors are over-expressed in different human tumors with high incidence and mortality rate, like small cell lung cancer, colon, prostate and pancreas carcinomas. For this reason, high affinity and stable NT peptides can have important applications as specific tumor-targeting agents.  We synthesized the short functional fragment NT(8-13) in a tetra-branched form (NT4), which was coupled during the synthesis to different units designed for tumor tracing or therapy.  Cell internalization of branched NT4 molecules together with NT receptor regulation and trafficking, were followed by confocal microscopy. NT4 conjugated to fluorescent probes was also used for NT receptor tracing in human specimens from colon cancer surgical resections. Comparison with normal tissues from the same patients showed a clear over-expression of NT receptor in a high percentage of tumors even at early differentiation stages.  Cytotoxicity of NT4 conjugated to methotrexate or to the photosensitizer chlorine e6, was tested on human colon adenocarcinoma cell lines. In both cases, conjugation to branched NT dramatically decreased non-specific toxicity of the drugs by inducing receptor-specific uptake of the toxic moiety by target cells.  NT4 conjugated to methotrexate was also tested in  in vivo  experiments using HT29 human colon adenocarcinoma xenografts in nude mice. Animals treated with NT4 conjugated to methotrexate showed a clear decrease in tumor growth with respect to untreated mice or mice treated with equimolar amount of the unconjugated drug.  Branched NT molecules are good candidates for the development of peptide tumor-targeting agents that might have the dual use of specific NT receptor tracing followed by targeted therapy of NT receptor-expressing tumors.  Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003; 24(4): 389-427.  Bracci L. et al. Synthetic peptides in the form of dendrimers become resistant to protease activity. J Biol Chem. 2003; 278(47): 46590-5.
Abstract 3599: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas
Authors: Claudia Merz, Sven Christian, Ashley Eheim, Henrik Seidel, Ralf Lesche, Merlin Luetke- Eversloh, Hanna Meyer, Steven Ferrara, Marcus Bauser, Andrea Haegebarth, Stefan Gradl, Andreas Janzer
Journal: Cancer Research (2019)

Abstract Colorectal carcinoma (CRC) is the third most common malignancy in the US, being responsible for approximately 50,000 deaths per year. The overall 5-year survival rates are high for localized disease (~90%), but low for metastatic disease (~14%), thereby underlining the high unmet medical need for novel therapeutics for CRC patients. DHODH is a key enzyme in the de novo pyrimidine synthesis, converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Since then, several publications have also described a role of DHODH in solid tumor indications. Herein we disclose the functional preclinical characterization of the novel DHODH inhibitor BAY 2402234 in CRC. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of CRC cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which is known to bypass DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. Interestingly, not all CRC cell lines are sensitive to the inhibitor. Similar to the in vitro observations, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in some, but not all, subcutaneous CRC xenograft models. A large CRC PDX in vivo screen revealed tumor growth inhibition in over 60% of the models in response to BAY 2402234 treatment. To elucidate the mode of action of BAY 2402234 in CRC we analyzed transcriptomic changes in CRC PDX models in vivo after single treatment with BAY 2402234, and identified several hundred differentially regulated genes at early time points. These in vivo PDX models were also used to explore potential effects of BAY 2402234 treatment on a large panel of metabolites. These preclinical results support the clinical evaluation of BAY 2402234 in patients with CRC, and such a clinical study is planned for early in 2019. Citation Format: Claudia Merz, Sven Christian, Ashley Eheim, Henrik Seidel, Ralf Lesche, Merlin Luetke- Eversloh, Hanna Meyer, Steven Ferrara, Marcus Bauser, Andrea Haegebarth, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas [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 3599.
A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue
Authors: Batika M.J. Rana, Eric Jou, Jillian L. Barlow, Noe Rodriguez-Rodriguez, Jennifer A. Walker, Claire Knox, Helen E. Jolin, Clare S. Hardman, Meera Sivasubramaniam, Aydan Szeto, E. Suzanne Cohen, Ian C. Scott, Matthew A. Sleeman, Chiamaka I. Chidomere, Sara Cruz Migoni, Jorge Caamano, Helle F. Jorgensen, Stefania Carobbio, Antonio Vidal-Puig, Andrew N.J. McKenzie
Journal: The Journal of Experimental Medicine (2019)

Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between the stroma and adipose-resident immune cells is less well understood. We identify that white adipose tissue–resident multipotent stromal cells (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals for sustaining ILC2. Indeed, we demonstrate that WAT-MSCs also support ICAM-1–mediated proliferation and activation of LFA-1–expressing ILC2s. Consequently, ILC2-derived IL-4 and IL-13 feed back to induce eotaxin secretion from WAT-MSCs, supporting eosinophil recruitment. Thus, MSCs provide a niche for multifaceted dialogue with ILC2 to sustain a type-2 immune environment in WAT.
Abstract 4310: Targeting Wnt signaling pathway using curcumin in metatstatic breast cancer cell lines
Authors: Nancy Ma, Patty Havard, Vinayak Shenoy, Anitha K. Shenoy
Journal: Cancer Research (2019)

Abstract Metastasis is the major reason for breast cancer-related deaths. The current treatment options for breast cancer include surgery, endocrine targeted therapy, radiation, chemotherapy and/or immunotherapy. However, even after treatment of the primary tumor at an early stage, breast cancer patients are at an increased risk of developing sudden metastases. Wnt signaling is a pivotal oncogenic pathway that contributes to human breast malignancy. High levels of Wnt ligands have been frequently detected in human breast cancers and accumulating evidence indicate a key role for the Wnt signaling pathway in the metastatic process. Curcumin, an active ingredient of turmeric has been shown to alter Wnt signaling as well as suppress metastasis in a variety of cancers. Here, we hypothesize that curcumin inhibits metastatic potential of breast cancer cell lines by targeting the Wnt signaling pathway. An initial dose dependent cytotoxic assay was performed with curcumin on two distinct breast cancer cell lines (epithelial and mesenchymal) to determine the optimum concentration for subsequent experiments. Our results indicate that curcumin imparts a dose dependent cytotoxic effect on both epithelial as well as mesenchymal breast cancer cell lines. Further, we observed that curcumin treatment alters the Wnt signaling pathway genes. Additional studies are warranted to confirm the effect of curcumin on Wnt signaling pathway and its role in combating proliferation and migration of breast cancer cells. Citation Format: Nancy Ma, Patty Havard, Vinayak Shenoy, Anitha K. Shenoy. Targeting Wnt signaling pathway using curcumin in metatstatic breast cancer cell lines [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 4310.
Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study
Authors: Tanios S Bekaii-Saab, Fang-Shu Ou, Daniel H Ahn, Patrick M Boland, Kristen K Ciombor, Erica N Heying, Travis J Dockter, Nisha L Jacobs, Boris C Pasche, James M Cleary, Jeffrey P Meyers, Rodwige J Desnoyers, Jeannine S McCune, Katrina Pedersen, Afsaneh Barzi, E Gabriela Chiorean, Jeffrey Sloan, Mario E Lacouture, Heinz-Josef Lenz, Axel Grothey
Journal: The Lancet Oncology (2019)
Limitations in the Methodology Assessing Subjective Data With Lack of Blinding in Mammography Screening—Reply
Authors: Philippe Henrot
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal
Longitudinal analysis of plasma ALK mutations during treatment with next-generation ALK inhibitors.
Authors: Ibiayi Dagogo-Jack, Marguerite Rooney, Rebecca Nagy, Subba Digumarthy, Emily Chin, Jennifer Ackil, Justin F. Gainor, Jessica Jiyeong Lin, Richard B. Lanman, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2019)

9068 Background: Next-generation ALK tyrosine kinase inhibitors (TKIs) are the cornerstone of management of ALK-positive (ALK+) lung cancer. Each ALK TKI has a unique spectrum of activity against distinct ALK kinase domain mutations (muts). Plasma genotyping is a promising strategy for identifying ALK muts at relapse on ALK TKIs. Methods: To detect ALK muts, we performed next-generation sequencing (Guardant360) of circulating tumor DNA from patients (pts) with ALK+ lung cancer relapsing on a second-generation (2 nd -gen) ALK TKI (n = 65) or the third-generation (3 rd -gen) TKI lorlatinib (n = 26). Results: Among 65 pts progressing on a 2 nd -gen TKI, 49 (75%) had only received one 2 nd -gen ALK TKI prior to analysis: n = 42 alectinib, n = 3 each brigatinib/ceritinib, and n = 1 ensartinib. We detected an ALK mut in 42/65 (65%) specimens at relapse, among which ALK G1202R (32%) and I1171X (23%) were the most common. Sixteen (25%) pts had ≥2 ALK muts at progression on a 2 nd -gen TKI. Among 26 pts progressing on lorlatinib (all of whom had previously relapsed on a 2 nd -gen ALK TKI), we identified ALK muts in 20 (76%), including 14 (54%) with ≥2 ALK muts. Detection of ≥2 ALK muts was more common at relapse on lorlatinib compared to a 2 nd -gen TKI (p = 0.013). To assess the evolution of ALK muts during treatment with different TKIs, we analyzed serial plasma specimens from 20 pts treated with sequential 2 nd -gen/2 nd -gen or 2 nd -gen/3 rd -gen TKIs. Among six pts who received alectinib followed by brigatinib, repeat plasma analysis at brigatinib progression revealed persistence of pre-brigatinib ALK muts in two pts (one L1196M and one G1202R), expansion of G1202R in one pt, and acquisition of new ALK muts in three pts. Among 14 pts who received a 2 nd -gen TKI followed by lorlatinib, 11 had persistence of pre-lorlatinib ALK muts and 8 acquired ≥1 additional ALK muts at lorlatinib progression. The most frequently acquired ALK mut was D1203N in four of eight cases. Conclusions: ALK resistance muts are prevalent at relapse on next-generation ALK TKIs and increase with each successive generation of ALK TKIs. These findings suggest that sequential therapy with increasingly potent ALK TKIs may select for compound ALK muts and/or fuel tumor heterogeneity.
Strategies to Avoid the “Hemolyzed” Physical Examination
Authors: Brian T. Garibaldi, Stephen W. Russell
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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 Internal Medicine journal
Low Free Sugar Diet in Adolescents With Nonalcoholic Fatty Liver Disease—Reply
Authors: Jeffery B. Schwimmer, Patricia Ugalde-Nicalo, Miriam B. Vos
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
Abstract 15587: Novel Stem Cell Niches Laminin 511 Promotes Functional Angiogenesis Through Enhanced Stem Cell Homing by Modulating "Stem Cell Beds" in the Failed Heart
Authors: Nagako Sougawa, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Junya Yokoyama, Mutsunori Kitahara, Akima Harada, Ryoko Sato-Nishiuchi, Kiyotoshi Sekiguchi, Yoshiki Sawa
Journal: Circulation (2017)

Background: The extracellular matrix (ECM) has great impacts not only on the architectural foundation of organ morphogenesis but also preservation in homeostasis and organ regeneration after injuri...