tbuckley/cabot-search huggingface dataset:
Revisiting cell–particle association in vitro: A quantitative method to compare particle performance
Authors: Matthew Faria, Ka Fung Noi, Qiong Dai, Mattias Björnmalm, Stuart T. Johnston, Kristian Kempe, Frank Caruso, Edmund J. Crampin
Journal: Journal of Controlled Release (2019)

Nanoengineering has the potential to revolutionize medicine by designing drug delivery systems that are both efficacious and highly selective. Determination of the affinity between cell lines and nanoparticles is thus of central importance, both to enable comparison of particles and to facilitate prediction of in vivo response. Attempts to compare particle performance can be dominated by experimental artifacts (including settling effects) or variability in experimental protocol. Instead, qualitative methods are generally used, limiting the reusability of many studies. Herein, we introduce a mathematical model-based approach to quantify the affinity between a cell–particle pairing, independent of the aforementioned confounding artifacts. The analysis presented can serve as a quantitative metric of the stealth, fouling, and targeting performance of nanoengineered particles in vitro. We validate this approach using a newly created in vitro dataset, consisting of seven different disulfide-stabilized poly(methacrylic acid) particles ranging from ~100 to 1000 nm in diameter that were incubated with three different cell lines (HeLa, THP-1, and RAW 264.7). We further expanded this dataset through the inclusion of previously published data and use it to determine which of five mathematical models best describe cell–particle association. We subsequently use this model to perform a quantitative comparison of cell–particle association for cell–particle pairings in our dataset. This analysis reveals a more complex cell–particle association relationship than a simplistic interpretation of the data, which erroneously assigns high affinity for all cell lines examined to large particles. Finally, we provide an online tool (http://bionano.xyz/estimator), which allows other researchers to easily apply this modeling approach to their experimental results.
Abstract 3712: Proliferative and invasive colorectal tumors in pet dogs provide unique insights into human colorectal cancer
Authors: Jin Wang, Tianfang Wang, Yanfang Sun, Yuan Feng, William C. Kisseberth, Carolyn J. Henry, Irene Mok, Susan E. Lana, Kevin Dobbin, Nicole Northrup, Elizabeth W. Howerth, Shaying Zhao, Houjian Cai
Journal: Cancer Research (2019)

Abstract Spontaneous tumors in pet dogs represent a valuable but undercharacterized cancer model. To better use this resource, we performed an initial global comparison between proliferative and invasive colorectal tumors from 20 canine cases and evaluated their molecular homology to human colorectal cancer (CRC). We sequenced 15 canine intestinal samples for WGS and 26 for RNA-seq. We investigated alterations in the genome and transcriptome, using state-of-the-art analysis tools. We aslso investigated their microbiome, by mapping WGS and RNA-seq read pairs that could not be placed onto the canine genome to two microbial genome databases: The Human Microbiome Project database and all bacterial genomic sequences. We performed the same analysis with TCGA (The Cancer Genome Atlas) colon cancer data. Based on our analysis, proliferative canine tumors harbor overactivated WNT/β-catenin pathways and recurrent CTNNB1 (β-catenin) mutations S45F/P, D32Y and G34E. Invasive canine tumors harbor prominent fibroblast proliferation and overactivated stroma. Both groups have recurrent TP53 mutations. We observed three invasion patterns in canine tumors: collective, crypt-like and epithelial-mesenchymal transition (EMT). We detected enriched Helicobacter bilis and Alistipes finegoldii in proliferative and crypt-like tumors, but depleted mucosa-microbes in the EMT tumor. Additionally, guided by our canine findings, we classified 79% of 478 human colon cancers from TCGA into four subtypes: primarily proliferative, or with collective, crypt-like or EMT invasion features. Their molecular characteristics match those of canine tumors. We showed that consensus molecular subtype 4 (mesenchymal) of human CRC should be further divided into EMT and crypt-like subtypes, which differ in TGF-β activation and mucosa-microbe content. Our canine tumors share the same pathogenic pathway as human CRCs. Dog-human integration identifies three CRC invasion patterns and improves CRC subtyping. Citation Format: Jin Wang, Tianfang Wang, Yanfang Sun, Yuan Feng, William C. Kisseberth, Carolyn J. Henry, Irene Mok, Susan E. Lana, Kevin Dobbin, Nicole Northrup, Elizabeth W. Howerth, Shaying Zhao, Houjian Cai. Proliferative and invasive colorectal tumors in pet dogs provide unique insights into human colorectal cancer [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 3712.
Abstract 3872: Targeting multi-functional ERK-protein complexes <i>in vivo</i>
Authors: Tamer S. Kaoud, William H. Johnson, Nancy D. Ebelt, Andrea Piserchio, Diana Zamora-Olivares, Sabrina V. Ravenstein, Jacey R. Pridgen, Ramakrishna Edupuganti, Rachel Sammons, Micael Cano, Mangalika Warthaka, Pengyu Ren, Eric V. Anslyn, Kenneth Y. Tsai, Ranajeet Ghose, Kevin N. Dalby
Journal: Cancer Research (2019)

Abstract Mutations in pathways that enhance the activity of ERK1 and ERK2 are frequently present in human cancers, reflecting their important roles in tumor initiation, and progression. This notion is reinforced by observations in BRAF V600E mutant melanoma where the majority of the mechanisms of resistance to FDA-approved combination therapies targeting BRAF and MEK involve reactivation of ERK1 and ERK2. Recently, the direct targeting of the ERK enzymes using ATP-competitive inhibitors has emerged as an attractive strategy to overcome acquired resistance to current combination therapies. The ERK enzymes employ unique mechanisms of molecular recognition to engage protein components of the MAPK pathway. Here we report the potent targeting of an ERK-protein docking interaction by a small molecule thiotriazole, which abrogates ERK signaling in vivo. The thiotriazole binds covalently to a highly conserved cysteine residue within the D-recruitment site of ERK1/2 with more than a 100-fold discrimination over other MAPKs (e.g. JNK1/2, p38MAPKs and ERK5). Treatment of various BRAF-inhibitor naive or inhibitor-resistant melanoma cell lines expressing BRAF V600E with the thiotriazole for 2 hours induces dose-dependent inhibition of ERK activation and downstream signaling. Inhibition is maintained for up to 5 hours following thiotriazole washout and induces apoptosis and growth inhibition. Treatment of mice carrying a BRAFV600E A375 melanoma xenograft with the thiotriazole blocked tumor growth. Transient expression of a mutant form of ERK2, which is resistant to the thiotriazole, promotes survival of A375 and HEK 293 cells treated with thiotriazole. This study lays the foundation for developing a new modality for the treatment of solid tumors driven by excessive ERK signaling. Citation Format: Tamer S. Kaoud, William H. Johnson, Nancy D. Ebelt, Andrea Piserchio, Diana Zamora-Olivares, Sabrina V. Ravenstein, Jacey R. Pridgen, Ramakrishna Edupuganti, Rachel Sammons, Micael Cano, Mangalika Warthaka, Pengyu Ren, Eric V. Anslyn, Kenneth Y. Tsai, Ranajeet Ghose, Kevin N. Dalby. Targeting multi-functional ERK-protein complexes in vivo [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 3872.
Abstract 16328: Difference Between Heart Failure With Preserved Ejection Fraction (HFpEF) and Reduced Ejection Fraction (HFrEF) Patients After Coronary Artery Bypass Grafting (CABG): A National Population-Based Cohort Study
Authors: Ujjwal Rastogi, Bing Yue, Chayakrit Krittanawong, Diana Otero, Sagar M Reddy, Priyanka Rastogi, Jossef Amirian, Carlos Gongora, Yashasvi Chugh, Ramya Kallur, Noah Moss, Johanna Contreras, Sean Pinney, John Puskas, Jagat Narula
Journal: Circulation (2018)

Introduction: Coronary artery disease is equally prevalent in patients with HFpEF and HFrEF patients. Though we have made tremendous advancement in HFrEF, we have not yet achieved desirable outcome...
Abstract 2076: Targeting vulnerable aberrant cancer-associated pathways by rationalized triple combination regimens to effectively control urothelial carcinoma cells in vitro and in vivo
Authors: Hwa-Chain R. Wang, Pawat Pattarawat, Jinquan Wang, Robert Donnell
Journal: Cancer Research (2019)

Abstract Urinary bladder cancer (UBC) is the fifth-most common cancer in the United States, and urothelial carcinomas (UCs) account for more than 90% of UBCs. Although current therapies are effective in the short-term treatment of UCs, the high tendency (&amp;gt;50%) for them to recur and progress to life threatening, advanced muscle-invasive UCs requires life-long surveillance with extended medical care. Thus, it still requires extensive therapeutic development to achieve an effective control of UC recurrence and improve the response rate and overall survival for UC patients. To develop effective and safe regimens to control the development and recurrence of advanced UCs, we investigated the efficacy of rationalized combination regimens in controlling UC cells in vitro and UC cell-derived xenografts (CDXs) in vivo. Our in vitro studies identified a triple combination of gemcitabine, romidepsin, and cisplatin, which are all FDA-approved anticancer agents, effective in synergistically inducing death and reducing drug resistance of various UC cell lines. Our studies also revealed that UC-associated aberrant pathways, including mitochondrial reactive oxygen species (ROS) and the ERK-Nox pathway, which were already induced in UC cells, were enhanced by the triple combination regimen to play essential roles for inducing apoptosis and reducing resistance. We also detected that the unfolded protein response played a role in modulating cell death induced by the regimen. Our in vivo studies used a tolerable protocol for administering combination regimens into animals. Our studies verified the efficacy of the triple combination gemcitabine plus romidepsin and cisplatin regimen, versus double combination regimens, in controlling UC CDXs in immune-deficient mice. In conclusion, our studies indicated that a rationalized triple combination of gemcitabine plus romidepsin and cisplatin regimen was more effective than double combination regimens in modulating UC-associated vulnerable aberrant pathways and controlling UC tumor development and recurrence in animals with low tolerable/ reversible adverse effects. Thus, the triple combination gemcitabine plus romidepsin and cisplatin regimen should be promptly considered as an advanced treatment over the conventional double combination gemcitabine plus cisplatin regimen in clinical trials in order to control advanced UCs. Citation Format: Hwa-Chain R. Wang, Pawat Pattarawat, Jinquan Wang, Robert Donnell. Targeting vulnerable aberrant cancer-associated pathways by rationalized triple combination regimens to effectively control urothelial carcinoma cells in vitro and in vivo [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 2076.
Characteristics and outcomes of Philadelphia chromosome-negative myeloproliferative neoplasm in a tertiary institute in India: An ambispective study.
Authors: Kamal Raj Soti, Lalit Kumar, Renu Saxena, Sameer Bakhshi, Ajay Gogia, Prabhat Singh Malik, Ranjit Sahoo, Sudha Sazawal
Journal: Journal of Clinical Oncology (2019)

e18553 Background: Philadelphia chromosome (Ph) negative Myeloproliferative neoplasm (MPN) is a rare heterogeneous group of clonal hematological malignancy. We aim to describe the clinico-pathological features, treatment, outcomes and complications of this disorder. Methods: It is an ambispective study. All Ph negative MPN patients registered during 2001 to 31st December 2015 at our institute were reviewed for demographic data, diagnosis based on WHO 2008 criteria, treatment, complications and outcomes. SPSS software was used. Results: There were 55 patients registered with PMF (37), ET (9), PV (7), CNL (1) and MPN-U (1). PMF showed median age 51.2 years (23-70), male: female ratio of 1.46, symptomatic (36), splenomegaly (29), mean hemoglobin 9.7 gm/dl (3-16), JAK2 mutation positive (14), CALR mutation positive (1). Most of the patients were DIPSS intermediate-1 risk 22 (59.4%) grouping. They received hydroxyurea (13), steroids (9), ruxolitinib (6), immunomodulators/steroids (4), aspirin (3), allogeneic stem cell transplantation (2), interferon (1), radiation (1), danazol (1) and observation (1). Median OS was not reached. OS at 5 years is 84% (95% CI 70% to 98%). Survival probability at 36 months is significant for circulating blasts &lt;1% and high bone marrow fibrosis but not significant on multivariate analysis. Progression probability at 36 months is significant for circulating blast &lt;1% and high DIPSS score but not significant in multivariate analysis. PV showed median age 58 years (23-70), male: female ratio 6:1, symptomatic (7), splenomegaly (6), mean hemoglobin 18.4 gm/dl (16.6-21.5), JAK2 mutation positivity (5), low risk (2), high risk (5). They received hydroxyurea (6), phlebotomy (3) and aspirin (1). Five out of 7 patients are in stable condition. ET showed median age 39 years (24-72), male: female ratio 2:1, symptomatic (4), splenomegaly (2), mean hemoglobin 12.2 gm/dl (7.5-15.4), JAK2 mutation positivity (4), low risk (7) and high risk (2). They received aspirin (6), hydroxyurea (5), and observation (1). Three patients are in stable condition. CNL (1) developed pneumothorax and was lost to follow up. MPN-U (1) received hydroxyuea. Seven died due to pneumonia (5), transfusion hypersensitivity (1) and AML transformation (1). Conclusions: PMF is the most common Ph negative MPN in our institute with DIPSS intermediate-1 being the most common risk group. At a median follow up of 36 months overall survival at 5 years is 84%.
Hereditary Persistence of Fetal Hemoglobin
Authors: T. H. J. Huisman, W. A. Schroeder, S. Charache, Nicholas C. Bethlenfalvay, N. Bouver, J. Roger Shelton, Joan Balog Shelton, Gerald Apell
Journal: New England Journal of Medicine (1971)

The ratio of the Gγ to Aγ chains of human fetal hemoglobin was determined in 30 members of three Negro families. Family members with four types of condition were studied: those who were heterozygotes and those who were homozygotes for the hereditary persistence of fetal hemoglobin, those who had β-thalassemia trait, and those who had both β-thalassemia trait and the hereditary persistence of fetal hemoglobin. The results from heterozygotes with the hereditary persistence of fetal hemoglobin or with β-thalassemia agree with previous data from other subjects of these types. The results from homozygotes for the hereditary persistence of fetal hemoglobin suggest that an unknown factor alters the expression of the γ genes as compared to that of the ordinary heterozygotes. Increased synthesis of fetal hemoglobin in persons with a combination of the hereditary persistence of fetal hemoglobin and β-thalassemia may be directed by the β-thalassemia gene.
Abstract 2009: Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular invasion and enhances cell death induced by DNA damaging chemotherapies
Authors: Xuanmao Jiao, Min Wang, Richard G. Pestell
Journal: Cancer Research (2019)

Abstract Purpose of the study. To assess binding and functional interaction of the humanized monoclonal antibody to CCR5 (Leronlimab) with human breast cancer cell lines. The G protein coupled receptor CCR5, is normally expressed on a subset of T cells and serves as a co-receptor for HIV infection. During malignant transformation CCR5 expression is known to increase in a number of cancers (breast cancer (BCa), prostate cancer, colon cancer, melanoma). CCR5 targeted cancer clinical trials using small molecular inhibitors opened to accrual in late 2018. CCR5 is expressed in &amp;gt;50% of human BCa, primarily in triple negative BCa. Its expression in human BCa correlates with poor outcome and CCR5+ BCa epithelial cells have characteristics of cancer stem cells, forming mammospheres and initiating tumors with &amp;gt;60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5 negative BCa cells promotes tumor metastases and induces DNA repair gene expression and activity. The CCR5 inhibitor Leronlimab has been used for treatment of &amp;gt;550 patients HIV, including meeting its primary endpoints in a phase III study, without significant adverse events reported. Results. Leronlimab bound to CCR5 expressed in human breast cancer cell lines with 98% efficiency. Leronlimab abrogated CCL5 induced Ca+2 flux and blocked 3-d matrigel invasion of MDA-MB-231 cells. Leronlimab also augmented cell killing by DNA damage inducing agents Doxorubicin. Conclusions. Leronlimab binds CCR5 in BCa cells, blocking breast cancer cellular invasion and augmenting cell killing by DNA damage inducing chemotherapies. As CCR5 augments DNA repair and is expressed selectively on cancerous but not normal breast epithelial cells, Leronlimab may enhance the tumor specific activities of DDR-based treatments, allowing a reduction in dose of standard chemotherapy and radiation. Citation Format: Xuanmao Jiao, Min Wang, Richard G. Pestell. Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular invasion and enhances cell death induced by DNA damaging chemotherapies [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 2009.
Abstract 4650: TOPK is a prognostic marker and therapeutic target in skin carcinogenesis
Authors: Eunmiri Roh
Journal: Cancer Research (2019)

Abstract Solar ultraviolet (sUV) is linked to development of cutaneous squamous cell carcinoma (cSCC) as a non-melanoma skin cancer (NMSC). Actinic keratosis (AK), induced by sUV irradiation, acts as precursor to cutaneous squamous cell carcinoma (cSCC) and is a pre-malignant skin lesion characterized with an abnormal proliferation of atypical keratinocytes confined to the epidermis of the skin. Therefore, to identify the major signaling molecules in the prevention, development and metastasis of cSCC is a critically important task. Here, we suggested a promising protein target, T-LAK cell-originated protein kinase (TOPK) as an active form of MEK1 continuously phosphorylating downstream targets, which appears to be critical in mediating skin carcinogenesis. We detected high levels of total and phosphorylated TOPK protein expression in SCC, and phosphorylated TOPK levels were also markedly higher in AKs and SCCs from patients compared to matched normal skin. Inflammation is known to contribute to tumor development and thus we examined the effect of a 2-minimal erythema dose (MED) of solar stimulated light (SSL) exposure in clinical human skin samples. Our results indicated that acute SSL irradiation increased epidermal thickness as a feature of inflammation and also enhanced total protein and phosphorylation levels of TOPK in human skin in a time-dependent manner. TOPK phosphorylation in human precancerous HaCaT keratinocytes was also increased by SSL irradiation in a dose- and time-dependent manner. Interestingly, TOPK knockout (TOPK-/-) SKH1 (Crl: SKH1-Hrhr) hairless mice showed no tumors on SSL-exposed skin tissues. In contrast, wild-type (TOPK+/+) control SKH1 hairless mice treated with SSL showed increased tumor volume and number. Furthermore, TOPK-/- mice showed base levels of epidermal thickness similar to the SSL-unexposed control group and the Ki-67 proliferation marker was decreased in SSL-exposed TOPK-/- mouse skin compared to SKH1 TOPK+/+ mice. Notably, levels of the anti-apoptotic protein Bcl-2 were decreased in TOPK-/- mice, compared to SSL-treated TOPK+/+ mice. Moreover, our results indicated that phosphorylated and total TOPK protein levels in SCC metastasized to skin or lymph nodes were significantly higher compared to human SCC primary tumors. These results indicated that phosphorylated and total TOPK proteins are associated with both SCC development and metastasis. Thus, molecular targeting of TOPK could be an effective approach in the clinic to treat or prevent cSCC. Citation Format: Eunmiri Roh. TOPK is a prognostic marker and therapeutic target in skin carcinogenesis [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 4650.
High risk patients with diffuse large B cell lymphoma are not enrolled on clinical trials.
Authors: Alfadel Alshaibani, Christina Lee, Sarah Camp Rutherford, Kah Poh Loh, Andrea M Baran, Carla Casulo, Paul M. Barr, Jonathan W. Friedberg, Patrick Michael Reagan
Journal: Journal of Clinical Oncology (2019)

e19058 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. In this study, we explore reasons for non-enrollment in clinical trials for DLBCL and implications on trial design and interpretation. Methods: This is a retrospective analysis of patients (pts) with a pathological diagnosis of DLBCL or high grade B-cell lymphoma (HGBL) at University of Rochester (4/14-6/16) and New York-Presbyterian Hospital/Weill Cornell Medicine (NYP/WCM) (4/14-4/17).Ten clinical trials were opened during this time. Participants were divided into 3 groups: those treated in trial, those not enrolled in trial because of need for urgent treatment, and those not enrolled in trial for any other reason. We used a center-stratified Cox proportional hazards model to estimate association of trial enrollment with progression-free survival (PFS; time from start of treatment until progression/death or the last date the pt was known to be progression free) and overall survival (OS). Results: We identified 263 pts; 17% (n = 45) enrolled in a trial. Reasons for non-enrollment included not meeting eligibility criteria (n = 98), physician choice (n = 50), and pt choice (n = 38). For 32 pts, reasons were unclear. Of the 50 pts who were not enrolled because of physician choice, the primary reason for non-enrollment was the need for urgent treatment (n = 46). Pts who needed urgent treatment had higher risk clinical features compared with pts in trial (Table). Compared with those treated in trial and those not enrolled in trial for any other reason, those not enrolled in trial due to need for urgent treatment had an inferior PFS (HR 2.61, 95% CI 1.23–5.16) and OS (HR 2.27, 95% CI 1.21–4.06). Conclusions: At 2 academic institutions, 52% of patients with DLBCL or HGBL required urgent chemotherapy and failed to enroll on trials. Exclusion of such patients limits the applicability and generalizability of clinical trials in DLBCL. This barrier must be overcome so clinical trials may better reflect true DLBCL demographics. [Table: see text]