tbuckley/cabot-search huggingface dataset:
Abstract 2082: Fc-FcγR interaction impacts the clearance and antitumor activity of antibody-drug conjugates in NSG mice
Authors: Fu Li, Michelle Ulrich, Joshua Hunter, Lori Westendorf, Devra Olson, Cassie Baker Lee, Dennis Benjamin, Che-Leung Law
Journal: Cancer Research (2016)

Abstract Majority of preclinical efficacy studies for cancer therapeutics are performed on tumor models implanted in immune-deficient mouse strains, including athymic nude, severe combined immunodeficiency (SCID), or NOD-SCID/IL2Rgamma null (NSG) mice. To better understand the correlation between drug exposure and preclinical antitumor activity of biologics, we evaluated the pharmacokinetic (PK) profiles of antibodies and antibody-drug conjugates (ADC) in four strains of mice commonly used in cancer research, including BALB/c, athymic nude, SCID, and NSG. To our surprise, antibodies and ADCs had an abnormally short serum half-life in NSG mice, compared to other strains of mice. We hypothesized that the fast clearance from plasma in NSG mice may reduce the overall exposure of xenografts to the ADCs, resulting in underestimation of antitumor activity. This was confirmed by comparing cAC10-vcMMAE in CD30+ Karpas-299 tumors implanted in either SCID mice or NSG mice. A single dose of 1 mg/kg cAC10-vcMMAE ADC resulted in complete remission of Karpas-299 tumors implanted in SCID mice (5/5). In contrast, the same treatment regimen had no effect on Karpas-299 tumors implanted in NSG mice (0/5). This observation suggests indeed the shortened exposure penalizes ADC efficacy in NSG models. We then hypothesized that the fast clearance of ADCs from plasma in NSG mice could be mediated by Fc-FcγR interaction; compromising this interaction may improve the serum half-lives of antibodies and ADCs and thus enhance ADC-mediated antitumor effects in NSG mice. To test this, we utilized a mutant antibody with the amino acid substitutions of E233P:L234V:L235 in its Fc domain that result in significantly reduced FcγR binding (G1V1). These mutations restored the serum exposure in NSG mice to that level comparable to other strains of mice. As a result, treatment of 1 mg/kg cAC10G1V1-vcMMAE led to tumor remission in Karpas-299 tumors grown in NSG mice, correlating with extended exposure. In parallel, pretreatment with human IV immunoglobulin also enhanced ADC exposure and antitumor activity in the NSG mice. In summary, these results suggest preclinical PK/PD assessment should be performed in the same strains of mice, especially when NSG xenograft models are used to evaluate activities. Moreover, reduced FcγR binding may enhance ADC exposure and allow a better assessment of therapeutic potential of biologics in NSG-based xenograft models. Citation Format: Fu Li, Michelle Ulrich, Joshua Hunter, Lori Westendorf, Devra Olson, Cassie Baker Lee, Dennis Benjamin, Che-Leung Law. Fc-FcγR interaction impacts the clearance and antitumor activity of antibody-drug conjugates in NSG mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2082.
C5 Polymorphism in a Dutch Patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) and No Asian Ancestry, Resistant to Eculizumab, but in Vitro Sensitive to Coversin
Authors: Saskia Langemeijer, Jun-Ichi Nishimura, Wynne Weston-Davies, Miles A Nunn, Yuzuru Kanakura, Ian J Mackie, Petra Muus
Journal: Blood (2015)
Health and Psychosocial Outcomes of a Telephonic Couples Behavior Change Intervention in Patients With Poorly Controlled Type 2 Diabetes: A Randomized Clinical Trial
Authors: Paula M. Trief, Lawrence Fisher, Jonathan Sandberg, Donald A. Cibula, Jacqueline Dimmock, Danielle M. Hessler, Patricia Forken, Ruth S. Weinstock
Journal: Diabetes Care (2016)

OBJECTIVE To compare glycemic control and secondary outcomes of a 4-month telephonic couples behavioral intervention to individual intervention, and to education, for adults with type 2 diabetes. RESEARCH DESIGN AND METHODS A randomized trial with the following three arms: couples calls (CC) (n = 104); individual calls (IC) (n = 94); and diabetes education (DE) (n = 82). All arms had self-management education (two calls). CC and IC had 10 additional behavior change calls. CC addressed collaboration and relationships/communication. Participants consisted of 280 couples, among whom one partner had type 2 diabetes and an A1C level ≥7.5%. Blinded assessments occurred at 4, 8, and 12 months. The primary outcome was change in A1C; and secondary outcomes were BMI, waist circumference, blood pressure, depressive symptoms, diabetes self-efficacy, and diabetes distress. RESULTS Patients had a mean age of 56.8 years; 61.6% were male, and 30.4% were minorities. The baseline mean A1C level was 9.1%. Intention-to-treat analyses found significant A1C reductions for all (12 months: CC −0.47%, IC −0.52%, DE −0.57%), with no differences between arms. Preplanned within-arm analyses were stratified by baseline A1C tertiles: lowest tertile (7.5–8.2%), no change from baseline; middle tertile (8.3–9.2%), only CC led to significantly lower A1C level; and highest tertile (≥9.3%), significant improvement for all interventions. For BMI, CC showed significant improvement, and CC and DE led to decreased waist circumference. The IC group showed greater blood pressure improvement. Results for secondary psychosocial outcomes favored the CC group. CONCLUSIONS In adults with poorly controlled type 2 diabetes, a collaborative couples intervention resulted in significant, lasting improvement in A1C levels, obesity measures, and some psychosocial outcomes. For those with exceedingly high A1C levels, education alone was beneficial, but additional intervention is needed to achieve glycemic targets.
Abstract 4837: Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents
Authors: Aleem Gangjee, Farhana Islam, Tasdique Mohammad Quadery, Susan L. Mooberry, Anja Bastian, Michael A. Ihnat
Journal: Cancer Research (2016)

Abstract Microtubules, attractive targets for drug development as anticancer agents, play vital roles in multiple aspects of cellular metabolism. These agents have been successfully used in the clinic for the treatment of various cancers. However, the utility of such agents are often limited by the emergence of tumor resistance due to overexpression of P-glycoprotein and/or âIII-tubulin. Tumor angiogenic mechanisms are important for tumor growth and metastasis are inhibited by antiangiogenic agents (AAs). AAs are usually cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of antiangiogenic agents with antitubulin agents have been particularly successful. Recently, we reported water-soluble tubulin targeting pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidine analogs as antitumor agents, that circumvent drug resistance. These analogs also possess RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. To further explore the activity of these dual RTK/tubulin inhibitors we designed isosteric thieno[2,3-d] pyrimidine and thieno[3,2-d]pyrimidine analogs which increased microtubule depolymerizing potency by 14 to 24-fold (AG95 IC50 = 7.0 ± 2.7 nM, AG370 IC50 = 7.6 ± 2.1 nM) compared with the lead compounds (AG85 IC50 = 96.6 ± 5.3 nM, AG20 IC50 = 183 ± 3.4 nM). Substitution at the 4-anilino position of both these scaffolds were also explored with various moieties to afford the 6-methoxy-tetrahydroquinoline moiety which possess the optimum balance of microtubule depolymerizing activity (AG372 IC50 = 4.3 ± 1.6 nM, AG337 IC50 = 3.4 ± 0.9 nM,) and RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. These two compounds demonstrated excellent inhibition for EGFR (IC50 = 12.6 ± 1.2 nM, 28.5 ± 3.9 nM), VEGFR-2 (25.2 ± 7.2 nM, 216.1 ± 18.6 nM) and PDGFRâ (IC50 = 25.6 ± 7.2 nM, 266.8 ± 35.4 nM) comparable to the standard clinically used agents. These attributes of the 4-N-substituted thieno pyrimidines provides the impetus for further development of these compounds as dual acting targeted antitumor agents. Citation Format: Aleem Gangjee, Farhana Islam, Tasdique Mohammad Quadery, Susan L. Mooberry, Anja Bastian, Michael A. Ihnat. Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4837.
Denosumab in patients with bone metastases from prostate, breast, and other cancers and elevated urinary N-telopeptide (uNTx) during intravenous bisphosphonate (IV BP) therapy: Final results of a randomized, phase II study
Authors: K. Fizazi, A. Lipton, X. Mariette, T. Suarez, J. Body, Y. Rahim, J. R. Gralow, G. Gao, L. Wu, S. Jun
Journal: Journal of Clinical Oncology (2008)

3596 Background: Patients (pts) with elevated levels of uNTx, representing excessive bone resorption, are at high risk for skeletal- related events (SREs), disease progression, and death (Coleman, J Clin Oncol 2005). Osteoclast-mediated bone resorption is regulated by RANKL, which can be inhibited by denosumab, a fully human monoclonal antibody against RANKL. Methods: Eligible pts (n = 111 with bone metastases or myeloma; on ≥ 8 weeks of IV BP before randomization; screening uNTx > 50 nM BCE/mM creatinine [Cr]) were stratified by tumor type and baseline uNTx and randomized to continue IV BP therapy every 4 weeks (Q4W; n = 37) or receive a subcutaneous injection of denosumab 180 mg Q12W (n = 36) or Q4W (n = 38). The primary endpoint was the proportion of pts with uNTx < 50 nM BCE/mM Cr (uNTx < 50) at week 13. Results: The median age was 62 years. The median time on prior IV BP (mostly zoledronate) was 5.3 months. Primary tumors included prostate (n = 50), breast (n = 46), and other/myeloma (n = 15). At week 13, the % (95% CI) of pts with uNTx < 50 was greater after treatment with denosumab vs IV BP: 71% (59%-81%) vs 29% (15%-46%; p < .001), respectively. Efficacy data were confirmed at week 25, representing the entire treatment period (table). Denosumab was associated with fewer SREs than IV BP (table). The most common adverse events (AEs) in the denosumab arms included bone pain, nausea, anemia, constipation, and asthenia. One serious AE of hypophosphatemia, possibly related to denosumab, was reported; no treatment-related death occurred. No neutralizing antibodies to denosumab were observed. Conclusions: Among pts with elevated uNTx despite previous IV BP therapy, denosumab normalized uNTx significantly more frequently than ongoing IV BP. The AE profile of denosumab was similar to that of cancer pts receiving treatment. These data support further evaluation of denosumab in phase III trials in oncology. Efficacy Endpoints IV Bisphospho- nate (n = 35) Denosumab 180 mg Q12W (n = 33) Denosumab 180 mg Q4W (n = 36) Pooled Denosumab (n = 69) Patients with uNTx < 50 nM BCE/mM Cr at week 25 - % (95% CI) 37% (22%-55%) 64% (45%-80%) 64% (46%-79%) 64% (51%-75%) Estimated time (days) to uNTx reduction to < 50 nM BCE/mM Cr - median (Q1, Q3) 65 (8, 141) 9 (4, 11) 10 (8, 11) 9 (8, 11) Estimated duration (days) of maintaining uNTx at <50 nM BCE/mM Cr - 25th percentilea 24 80 284 160 Patients experiencing skeletal-related events - n/N (%) 7/35 (20%) 4/35 (11%) 2/38 (5%) 6/73 (8%) aThe median duration was not achieved for the denosumab arms during the treatment period. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen
Changing the Narrative
Authors: Joshua Allen-Dicker
Journal: JAMA (2016)

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Psychotherapy — The Transformation of Meanings: Discussion Paper
Authors: J D Frank
Journal: Journal of the Royal Society of Medicine (1986)

This paper presents the hypothesis that psychotherapy seeks to produce changes in attitudes and behaviour through transformation of meanings. Patients come to psychotherapy because they are demoralized by the menacing meanings of their symptoms. The psychotherapist collaborates with the patient in formulating a plausible story that makes the meanings of the symptoms more benign and provides procedures for combating them, thereby enabling the patient to regain his morale. As a result, he feels better and functions more effectively, leading to progressive improvement. Various implications and limitations of this hypothesis are explored.
Inhibiting Mitochondrial DNA Ligase IIIα Activates Caspase 1–Dependent Apoptosis in Cancer Cells
Authors: Annahita Sallmyr, Yoshihiro Matsumoto, Vera Roginskaya, Bennett Van Houten, Alan E. Tomkinson
Journal: Cancer Research (2016)

Elevated levels of DNA ligase IIIα (LigIIIα) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIα inhibitor, L67, in combination with a poly (ADP-ribose) polymerase inhibitor. Because LigIIIα functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here, we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and nonmalignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIα in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA, and increased levels of mitochondrially generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1-dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells. Cancer Res; 76(18); 5431-41. ©2016 AACR.
Abstract 2442: EWS/FLI1 activates GLI1 indirectly through GLI2 in Ewing Sarcoma
Authors: Laura Christensen, William A. May
Journal: Cancer Research (2016)

Abstract GLI1 expression in Ewing tumors has been shown to be enhanced by EWS/FLI1 expression in both model transformation systems and in Ewing cell lines. In Ewing cells, GLI1 has been shown to produce significant phenotypic effects consistent with a role in Ewing tumor formation and propagation. Also consistent with an important role is the demonstrated correspondence between the transcriptional target sets of EWS/FLI1 and of GLI1 in Ewing tumor cells. The principal physiologic developmental regulator of GLI1 is the diffusible Sonic Hedgehog ligand which binds the cell surface tumor suppressor Patched with consequent activation of the transmembrane protein Smoothened. In Ewing tumors, the enhancement of GLI1 expression has been shown to be Hedgehog independent and to occur downstream of Smoothened. Indeed, evidence has been published that EWS/FLI1 directly activates the GLI1 promoter. While there is experimental evidence that GLI1 inhibition may be clinically useful in Ewing tumors, preclinical evidence for one inhibitory approach has been disappointing. Interestingly, direct transcriptional activation of GLI1 has not been demonstrated to be of significance in other most other physiologic or pathologic contexts. We speculated that direct transcriptional activation of GLI1 by EWS/FLI1 might be only part of the story in Ewing tumors. Since GLI2 is the most potent physiologic transcriptional activator of GLI1, we undertook to investigate the role of GLI2 in Hedgehog/GLI (HH-GLI) signaling in Ewing Tumors. We found that GLI2 is broadly expressed in Ewing tumors. Based on GLI2 overexpression and on shRNA knockdown of GLI2, we found that GLI2 expression increases GLI1 expression in Ewing cell lines. Via GLI2 knockdown, we have found that GLI2 has biologic effects similar to or greater than GLI1 in Ewing cells. Finally, we demonstrate that EWS/FLI1 enhances nuclear localization of GLI2, suggesting an additional indirect mechanism by which EWS/FLI1 activates HH-GLI signaling and GLI1 expression in Ewing tumors. These data indicate that GLI2 is an active player in HH-GLI pathway activation in Ewing tumors. They also suggest that measures which target GLI2 may have equal or greater efficacy to those aimed at GLI1. Citation Format: Laura Christensen, William A. May. EWS/FLI1 activates GLI1 indirectly through GLI2 in Ewing Sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2442.
Stromal Precursor Cells Characteristics In Patients With ALL Before and After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Irina N. Shipounova, Natalia Petinati, Natalia Sats, Alexey Bigildeev, Nina I. Drize, Larisa Kuzmina, Elena Parovichnikova, Valeriy Savchenko
Journal: Blood (2013)
Abstract 715: Adipose tissues derived exosomal microRNAs and their variants in ovarian cancer progression
Authors: Chi Lam Au Yeung, Tetsushi Tsuruga, Ngai Na Co, Tsz-Lun Yeung, Cecilia S. Leung, Kwong K. Wong, Samuel C. Mok
Journal: Cancer Research (2016)

Abstract Most ovarian cancers are diagnosed at an advanced stage when the tumor is widely metastatic. The 5-year survival drops to 50% for the cancer cases that spread beyond the pelvis to the omentum. However, the mechanisms underlying the effect of omental adipose tissue on ovarian cancer progression are poorly understood. Recent studies showed that exosomes also contain non-coding RNAs such as microRNAs (miRNAs). Thus, we hypothesize that the transfer of microRNAs and their variants from ovarian cancer-associated omental adipose tissues to ovarian cancer cells via exosomes may contribute to the nearby microenvironment for ovarian cancer metastasis and cancer progression. Ion Torrent next generation sequencing was performed on miRNAs isolated and enriched from exosomes and cell lysates of ovarian cancer cell lines (OVCA), the epithelial component of microdissected omental ovarian cancer tissues (CT), normal omental adipose tissues (OMN) and ovarian cancer-associated omental adipose tissues (OMT). By integrating the miRNA expression profiles, 65 miRNAs were expressed at significant higher levels in OMT-derived exosomes compared with those in OMN-derived exosomes and OVCA-derived exosomes. A set of miRNAs (miR-32a, miR-221 and miR320a), which had been implicated in controlling cell growth and chemoresistance, was identified. Also, the Ion Torrent results were validated and exosomal transfer of OMT-derived miRNAs was confirmed in vitro. The exosomal communication between adipose tissues and ovarian cancer cells in the omental tumor microenvironment is verified. The transferable miRNAs and their variants may remain functional in the recipient ovarian cancer cells and confer more aggressive phenotypes in these cells. Citation Format: Chi Lam Au Yeung, Tetsushi Tsuruga, Ngai Na Co, Tsz-Lun Yeung, Cecilia S. Leung, Kwong K. Wong, Samuel C. Mok. Adipose tissues derived exosomal microRNAs and their variants in ovarian cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 715.
Efficacy and cost-effectiveness of a specialist depression service versus usual specialist mental health care to manage persistent depression: a randomised controlled trial
Authors: Richard Morriss, Anne Garland, Neil Nixon, Boliang Guo, Marilyn James, Catherine Kaylor-Hughes, Richard Moore, Rajini Ramana, Christopher Sampson, Timothy Sweeney, Tim Dalgleish
Journal: The Lancet Psychiatry (2016)
Abstract 2522: S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs
Authors: KIn-Hoe Chow, Hee Jung Park, Joshy George, Andrew D. Gallup, Eric Neilson, Kyuson Yun
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is one of the most incurable human cancers, and the mesenchymal subtype of GBMs has the worst prognosis. The mesenchymal phenotype and glioma stem cells (GSCs) are associated with tumor recurrence and therapy resistance. While growing evidence suggests that tumor microenvironment modulates stemness and the mesenchymal phenotype, little is known about how these phenotypes are coordinately regulated. Here we report that S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. First, we show that S100a4 is a novel marker and a regulator of GBM TICs. Using genetically engineered mice and patient derived GBM tumorspheres, we show that S100a4 expression is enriched in TICs and that S100a4 function is critical for self-renewal of these cells. Furthermore, we demonstrate that selective ablation of S100a4+ cells in vivo is sufficient to block tumor growth. Second, we show that S100A4 regulates expression of EMT regulators, SNAIL2 and ZEB1, in addition to master transcriptional regulators of the mesenchymal signature genes (CEBPB/D, RUNX1, FOSL2, and BHLHE40), suggesting that S100A4 is an upstream (master) regulator of mesenchymal transition in GBMs. Third, we show that acidosis, a common environmental stress in malignant tumors, induces S100A4 and epithelial-mesenchymal transition (EMT) regulator expression. Importantly, S100A4 is required for acidosis-induced EMT and mesenchymal transition. Consistently, S100A4 expression is strongly associated with the mesenchymal subtype of GBMs, and S100A4 is an independent prognostic indicator for the mesenchymal subtype GBM patient survival. In summary, we show that S100A4 is a critical node in the molecular network that controls glioma stem cells and the mesenchymal phenotype, and propose that targeting S100A4 may simultaneously suppress mesenchymal transition and stemness of glioma cells, particularly in stressful tumor environments. Citation Format: KIn-Hoe Chow, Hee Jung Park, Joshy George, Andrew D. Gallup, Eric Neilson, Kyuson Yun. S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2522.