tbuckley/cabot-search huggingface dataset:
R16, a novel amonafide analogue, induces G2 arrest and apoptosis via poisoning topoisomerase II
Authors: Hong Zhu, Min Huang, Yi Chen, Ze-Hong Miao, Yu-Jun Cai, Jian Ding
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

770 

The naphthalimide derivative amonafide has been selected as an investigational anticancer drug for clinical trials by the National Cancer Institute in the National Institutes of Health. However, its metabolite N-acetyl-amonafide resulting from its N-acetylation on 5’-NH2 of the naphthyl ring by N-acetyltransferase 2 is a major challenging factor for its clinical future as this metabolite may lead to unpredictable, severe toxicity. To eliminate generation of such toxic acetylated metabolite(s), in this study, we substituted the 5’-NH2 with a heterocyclic group to the parent compound amonafide and thus obtained the novel amonafide analogue, 2-(2-dimethylamino)-6-thia-2-aza-benzo [def] chrysene-1, 3-diones (R16). Such substitution totally removed the site acted by N-acetyltransferase 2 and thereby the toxic threats subsequent to its catalytic transformation as on the parent amonafide. On the other hand, R16 also exhibited comparable in vitro and in vivo anticancer activities with amonafide, as shown in a panel of various human tumor cell lines and multidrug resistance cell lines and in mouse S-180 sarcoma and H22 hepatoma models. Mechanistic studies revealed that R16 functioned as a topoisomerase II (Top2) poison via trapping Top2-DNA cleavage complexes and binding to the ATPase domain of human Top2α. Using Top2 catalytic inhibitor aclarubicin, ATM/ATR kinase inhibitor caffeine and Top2-deficient HL-60/MX2 cells, we demonstrated that R16-triggered DNA double-strand breaks, tumor cell cycle arrest and apoptosis were in Top2-dependent manner. These data have uncovered that Top2 is the primary target for R16 in tumor cells and that its prominent antitumor capability is ascribed to the formation of Top2 cleavage complexes. We further explored the effects of R16 on cell cycle and apoptosis. Upon treatment of R16 at low doses, DNA double-strand breaks activated ATM, caused nuclear export of cyclin B1 and consequently resulted in evident G2 arrest in tumor cells. The ATM-Chk2 pathway played a central role in R16-driven G2 arrest. In contrast, higher doses of R16 induced apoptosis by stimulating cytochrome c release from the mitochondria and activating the death receptor pathway. Taken together, our strategy of substituting the 5’-NH2 of amonafide with a heterocyclic group yielded a resulting novel compound R16 with reduced toxicity and comparable anticancer activities. R16 as well as amonafide kills tumor cells, arrests cell cycle in G2 phase and induces apoptosis primarily by targeting Top2. Our data collectively reveal the potential value of R16 for further development as an anticancer drug.
Abstract 360: Differential Analysis of Thrombospondin Proteins in Cardiac Disease
Authors: Tobias G Schips, Nathan R Correll, Michelle A Sargent, Jeffery D Molkentin
Journal: Circulation Research (2015)

Thrombospondin (Thbs) proteins are multidomain, matricellular proteins comprised of 5 genes that each share similar domains and have been largely ascribed the same functional characteristics The Thbs protein family is divided in 2 subgroups based on multimerization as trimers, (group A: Thbs1 and 2), or as pentamers (group B: Thbs3, 4 and 5). Thbs proteins modulate aspects of cell- matrix interactions, and more recently we have shown that they can also serve an intracellular chaperone function along the secretory pathway in response to ER stress. Thbs1 and 2 can also alter angiogenesis and modulate MMP activity as well as TGFb activity. The overall aim of this study is to functionally compare the two Thbs subgroups and elucidate their involvement in cardiac homeostasis and disease. Hence we analyzed Thbs1 as a representative of group A and Thbs3 for group B. Cardiomyocyte specific overexpression of either Thbs1 or Thbs3 results in robust activation of an ATF6- dependent ER stress response, similar to our previous working published with Thbs4. However, Thbs1 overexpressing mice suffer from cardiomyopathy and die within 12 weeks. In contrast, Thbs3 overexpressing mice are completely normal at baseline and Thbs3 overexpression even increased survival rates after MI similar to Thbs4 from our previous work. However, Thbs3 hearts also showed increased chamber dilation after MI and lower heart function suggesting that Thbs3 also has maladaptive effects. In contrast to loss of Thbs4, which die within the first week of TAC mediated pressure overload, Thbs3 KO mice are protected from TAC induced hypertrophy. Moreover, the combination of Thbs3/4 dKO more closely phenocopies the effect of Thbs3 deletion, as these mice show a significant reduction in hypertrophy and lung congestion after long term TAC. This is the first study comparing the function of different Thbs isoforms in the heart, which suggests a novel role of Thbs3.
Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL
Authors: J R Brown, P Hillmen, S O’Brien, J C Barrientos, N M Reddy, S E Coutre, C S Tam, S P Mulligan, U Jaeger, P M Barr, R R Furman, T J Kipps, F Cymbalista, P Thornton, F Caligaris-Cappio, J Delgado, M Montillo, S DeVos, C Moreno, J M Pagel, T Munir, J A Burger, D Chung, J Lin, L Gau, B Chang, G Cole, E Hsu, D F James, J C Byrd
Journal: Leukemia (2017)

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.
LOTUS (NCT02162719): A double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC).
Authors: Rebecca Alexandra Dent, Sung-Bae Kim, Seock-Ah Im, Marc Espie, Sibel Blau, Antoinette R. Tan, Steven Isakoff, Mafalda Oliveira, Cristina Saura, Matthew Wongchenko, Amy V. Kapp, Wai Y. Chan, Stina M. Singel, Daniel J. Maslyar, Jose Baselga
Journal: Journal of Clinical Oncology (2017)

1009 Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation, including TNBC. Methods: Eligible patients (pts) had measurable inoperable locally advanced/metastatic TNBC previously untreated with systemic therapy. Pts were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumor PTEN status, and randomized 1:1 to P 80 mg/m 2 (d1, 8 &amp; 15) with either IPAT 400 mg or PBO (d1–21) q28d until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) in the ITT population and pts with PTEN-low tumors by IHC. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and overall survival in the ITT and IHC PTEN-low populations, efficacy in pts with PIK3CA/AKT1/PTEN-altered tumors by next-generation sequencing (NGS), and safety. Results: Baseline characteristics were generally balanced between arms. Efficacy is shown below. The most common grade ≥3 AEs (grouped terms) were diarrhea (23% IPAT+P vs 0% PBO+P; no grade 4 or colitis in either arm), neutropenia (18% vs 8%), asthenia (5% vs 6%), peripheral neuropathy (5% vs 5%) and pneumonia (5% vs 0%). More pts receiving IPAT+P than PBO+P had an AE leading to dose reduction of IPAT/PBO (21% vs 6%) or P (38% vs 11%) but median cumulative dose intensity was similar (IPAT/PBO: 99% vs 100%; P: 100% vs 100%). AEs led to IPAT/PBO discontinuation in 13% vs 11% of pts, respectively; 2 pts (3%) discontinued IPAT for grade 3 diarrhea. Conclusions: Adding IPAT to P for TNBC modestly improved PFS in the ITT pts. The effect was more pronounced in the prespecified subgroup with PIK3CA/AKT1/PTEN alterations, warranting further evaluation of IPAT in these pts. AEs were manageable. Clinical trial information: NCT02162719. [Table: see text]
Experience of implementing a novel random sampling BICR audit for investigator (INV)-assessed progression-free survival (PFS) in the PALOMA-3 trial.
Authors: Xin Huang, Ke Zhang, Nicholas C. Turner, Cynthia Huang Bartlett, Carla Giorgetti, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2017)

1058 Background: PFS has frequently been used as a primary endpoint for evaluating efficacy of anticancer therapies in randomized clinical trials. Given high correlation between INV and independent (BICR) assessments with respect to the relative treatment effect, a pre-planned BICR audit of INV progression assessment in a random subgroup of patients (pts) instead of a BICR review of all progression assessments can be an acceptable approach to verify the INV assessments and to evaluate the potential bias in INV PFS results. Methods: PALOMA-3 was a randomized, double blind, placebo (PCB) controlled, Ph 3 study with the primary objective of demonstrating the superiority of palbociclib (PAL) + fulvestrant (F) over PCB + F in women with HR+, HER2- metastatic breast cancer (MBC). The primary endpoint was INV assessed PFS. BICR assessment of PFS was performed with the use of a novel audit approach involving a random sample–based BICR to verify if the INV assessed PFS was accurate. A third-party core imaging laboratory performed the blinded review for a randomly selected subgroup of pts (~40%). NIH and PhRMA methods were used to evaluate the potential for bias in the INV PFS results. Results: PAL + F improved PFS in patients with HR+, HER2- MBC. The observed INV HR was 0.46 (95% CI: 0.36, 0.59; stratified 1-sided p &lt; 0.0001) in favor of PAL + F. The median PFS was 9.5 mo (95% CI: 9.2, 11.0) in the PAL + F arm and 4.6 mo (95% CI: 3.5, 5.6) in the PCB + F arm (Lancet Oncol. 2016; 17: 425–39). The estimated HR of the complete BICR data incorporating the information from the complete INV assessed PFS and the random sample audited BICR subgroup was 0.33 with the upper bound of the 1-sided 95% CI of 0.47. The results confirmed the INV assessed treatment effect and detected no INV bias in favor of PAL + F. Conclusions: PALOMA-3 is the first registrational trial to use a BICR audit and has received positive reviews from regulatory agencies. The experience of implementing the random sampling BICR audit in PALOMA-3 demonstrates that this approach can be used for randomized, double blind oncology trials with solid tumors where INV assessed PFS is the primary endpoint and a large treatment effect is targeted. Sponsor: Pfizer. Clinical trial information: NCT01942135.
Cellular stress response mechanisms as therapeutic targets of ginsenosides
Authors: Hong‐yi Qi, Li Li, Hui Ma
Journal: Medicinal Research Reviews (2017)

Ginseng, one of the most widely used traditional herbal medicines and dietary supplements, has historically been recognized as a tonic herb and adaptogen that can enhance the body's tolerance to various adversities. Ginsenosides are a diverse group of steroidal saponins that comprise the major secondary metabolites of ginseng and are responsible for its multiple pharmacological effects. Emerging evidence suggests that hormetic phytochemicals produced by environmentally stressed plants can activate the moderate cellular stress response mechanisms at a subtoxic level in humans, which may enhance tolerance against severe dysfunction or disease. In this review, we initially describe the role of ginsenosides in the chemical defense of plants from the genus Panax suffering from biotic and abiotic stress. Next, we summarize the diverse evolutionarily conserved cellular stress response pathways regulated by ginsenosides and the subsequent stress tolerance against various dysfunctions or diseases. Finally, the structure-activity relationship involved in the effect of ginsenosides is also analyzed. The evidence presented in this review implicates that ginseng as "the King of all herbs" could be regarded as a well-characterized example of the critical role of cellular stress response mechanisms in understanding the health benefits provided by herbal medicines from an evolutionary and ecological perspective.
A phase Ib dose escalation study of combined inhibition of IDO1 (GDC-0919) and PD-L1 (atezolizumab) in patients (pts) with locally advanced or metastatic solid tumors.
Authors: Howard A. Burris, Michael S. Gordon, Matthew David Hellmann, Patricia LoRusso, Leisha A. Emens, F. Stephen Hodi, Christopher Hanyoung Lieu, Jeffrey R. Infante, Frank Yung-Chin Tsai, Joseph Paul Eder, James M. Cleary, Danijela Jelovac, Amy L. Tsuhako, Lars Mueller, Ray Lin, Kari Morrissey, Sami Mahrus, Roland Morley, Andrea Pirzkall, Sarah Lindsey Davis
Journal: Journal of Clinical Oncology (2017)

105 Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.
The Effect of X Irradiation and Lowered Metabolic Rate on the Morphogenesis of Developing &lt;italic&gt;Melanoplus differentialis&lt;/italic&gt; Embryos
Authors: Theodore N. Tahmisian, Janet V. Passonneau, Dorothy M. Adamson
Journal: JNCI Journal of the National Cancer Institute (1954)

The Effect of X Irradiation and Lowered Metabolic Rate on the Morphogenesis of Developing Melanoplus differentialis Embryos Get access Theodore N. Tahmisian, Theodore N. Tahmisian Division of Biological and Medical Research, Argonne National Laboratory, Lemont, Ill. Search for other works by this author on: Oxford Academic PubMed Google Scholar Janet V. Passonneau, Janet V. Passonneau Division of Biological and Medical Research, Argonne National Laboratory, Lemont, Ill. Search for other works by this author on: Oxford Academic PubMed Google Scholar Dorothy M. Adamson Dorothy M. Adamson Division of Biological and Medical Research, Argonne National Laboratory, Lemont, Ill. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 14, Issue 4, February 1954, Pages 941–953, https://doi.org/10.1093/jnci/14.4.941 Published: 01 February 1954 Article history Received: 07 July 1953 Published: 01 February 1954
Change in physical activity from adolescence to early adulthood: a systematic review and meta-analysis of longitudinal cohort studies
Authors: Kirsten Corder, Eleanor Winpenny, Rebecca Love, Helen Elizabeth Brown, Martin White, Esther van Sluijs
Journal: British Journal of Sports Medicine (2017)

Objective To systematically review and meta-analyse how physical activity (PA) changes from adolescence to early adulthood (13–30 years). Data sources Seven electronic databases were searched: Medline, Embase, PsycInfo, SCOPUS, ASSIA, SPORTdiscus and Web of Science. Eligibility criteria for selecting studies English-language, longitudinal studies (from 01/1980 to 01/2017) assessing PA ≥twice, with the mean age of ≥1 measurement in adolescence (13–19 years) and ≥1 in young adulthood (16–30 years) were included. Where possible, data were converted to moderate-to-vigorous physical activity (MVPA) min/day, and meta-analyses were conducted between weighted mean differences (WMDs) in adolescence and adulthood. Heterogeneity was explored using meta-regression. Results Of 67 included studies, 49 were eligible for meta-analysis. PA was lower during adulthood than adolescence WMD (95% CI) −5.2 (−7.3 to –3.1) min/day MVPA over mean (SD) 3.4 (2.6) years; heterogeneity was high (I 2 &gt;99.0%), and no predictors explained this variation (all p&gt;0.05). When we restricted analysis to studies with data for males (n=29) and females (n=30) separately, there were slightly larger declines in WMD (−6.5 (−10.6 to –2.3) and −5.5 (−8.4 to −2.6) min/day MVPA) (both I 2 &gt;99.0%). For studies with accelerometer data (n=9), the decline was −7.4 (−11.6 to –3.1) and longer follow-up indicated more of a decline in WMD (95% CI) (−1.9 (−3.6 to –0.2) min/day MVPA), explaining 27.0% of between-study variation. Of 18 studies not eligible for meta-analysis, nine statistically tested change over time: seven showed a decline and two showed no change. Conclusion PA declines modestly between adolescence and young adulthood. More objective longitudinal PA data (eg, accelerometry) over this transition would be valuable, as would investigating how PA change is associated with contemporaneous social transitions to better inform PA promotion interventions. Registration PROSPERO ref:CRD42015030114.
Abstract 13754: Scar Burden and Left Ventricular Dyssynchrony on Myocardial Perfusion Imaging as Predictors of Antitachycardia Pacing Responsiveness in the Treatment of Ventricular Tachycardia
Authors: Akrivi Manola, William L Duvall, Dalia Giedrimiene, Alan W Ahlberg, Chandana Shekar, Jeffrey Kluger
Journal: Circulation (2015)

Background: Antitachycardia pacing (ATP) is the primary treatment for sustained ventricular tachycardia (VT), resulting in a reduction in ICD shocks. Patients who fail ATP have increased mortality compared to ATP responders. Myocardial scarring by cMR and left ventricular dysynchrony (LVD) by nuclear imaging are associated with a higher risk for VT. We hypothesized that scar and dyssynchrony can predict response to ATP. Methods: We identified 119 patients with sustained VT from 2008-2012, who received ICD therapy with preprogrammed ATP delivery and had a single photon emission computed tomography (SPECT) myocardial perfusion study. Semi-quantitative visual scoring with a 17-segment model was used and the summed stress, rest and difference scores were calculated to measure abnormal myocardium, scar and ischemia. LVD was measured in gated studies (n=59), using the established phase analysis (PA) methodology. Phase standard deviation (PSD) and histogram bandwidth (HBW) were compared between groups using chi-square analysis. Results: Of 119 patients (105 men, mean age: 75.8±18.2y), 82 (68%) had successful ATP. Normal myocardial perfusion was more commonly found in ATP-responders (10.5% vs. 19.8%, p=0.29). There was no difference in the presence of ischemia between the two groups. Phase SD (13.5±6.2 vs. 9.0±5.4, p=0.009) and HBW (54.5±27.1 vs. 37.9±25.2, p = 0.03) were significantly higher among ATP responders. In both a univariate and multivariate logistic regression analysis phase SD (OR, 95% CI: 1.85, 1.09-3.15, p=0.02) was an independent predictor of ATP success. Conclusions: LV dyssynchrony but not scar burden was associated with ATP responsiveness. These results are hypothesis generating for a role of LV dyssynchrony in the prediction of ATP responsiveness.
Routine blood tests are a basic screening tool for serious pathology
Authors: Keith Siau
Journal: BMJ (2017)

Faulkner and colleagues challenge the practice of routine blood tests, saying that they are a clinician’s “psychological support blanket” and have cost implications.1 I acknowledge that acute medicine is geared towards knee jerk diagnostics—medical patients are often referred from emergency departments with the usual gamut of blood tests, electrocardiogram, and chest x ray.

But, as a medical …