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Antitumor activity and toxicity of the indenoisoquinolines LMP400, LMP744 and LMP776 in Brca1-deficient murine orthotopic allograft model for ovarian cancer and synergy of LMP400 with olaparib. A-C. Antitumor activity of LMP400, LMP744, LMP776, olaparib alone and olaparib combination with LMP400 represented as tumor volume changes in individual mice. Single treatment experiment (A) and Combination study (C). B-D. Mice Body Weight changes for the corresponding experiments. Single treatment experiment (B) and Combination study (D).

CellMinerCDB snapshots (http://discover.nci.nih.gov/cellminercdb) demonstrating the correlations between the activity of the three clinical indenoisoquinolines and topotecan activity.

CellMinerCDB snapshots (http://discover.nci.nih.gov/cellminercdb) demonstrating the correlations between the activity of the three clinical indenoisoquinolines and SLFN11 expression in the NCI-60 (A-C) and in the GDSC (MGH-Sanger) panels of non-isogenic cancer cell lines. Each dot represents a cell line [59 cell lines are shown for the NCI-60 (A-C) and 712 cell lines are included in the GDSC plot (D). LMP compounds are listed by their NSC numbers in the NCI-60 panels A-C (LMP400 = NSC724998; LMP744 = NSC706744 and LMP776 = NSC725776). LMP744 a is also referred as MJ-III-65 in the GDSC (MGH-Sanger) database.

LMP400 activity values for all NCI-60 cell lines

LMP776 is synergistic with talazoparib in BRCA1-/- cells. Cell viability curves of talazoparib in DT40 WT (blue symbols and curves) and BRCA1-/- cells (red) with the indicated concentrations of LMP776. Open symbols and dashed lines correspond to talazoparib alone.

Purpose:Irinotecan and topotecan are used to treat a variety of different cancers. However, they have limitations, including chemical instability and severe side effects. To overcome these limitations, we developed the clinical indenoisoquinolines: LMP400 (indotecan), LMP776 (indimitecan), and LMP744. The purpose of the study is to build the molecular rationale for phase II clinical trials.Experimental Design:CellMinerCDB (http://discover.nci.nih.gov/cellminercdb) was used to mine the cancer cell lines genomic databases. The causality of Schlafen11 (SLFN11) was validated in isogenic cell lines. Because topoisomerase I (TOP1)-mediated replication DNA damage is repaired by homologous recombination (HR), we tested the “synthetic lethality” of HR-deficient (HRD) cells. Survival and cell-cycle alterations were performed after drug treatments in isogenic DT40, DLD1, and OVCAR cell lines with BRCA1, BRCA2, or PALB2 deficiencies and in organoids cultured from prostate cancer patient-derived xenografts with BRCA2 loss. We also used an ovarian orthotopic allograft model with BRCA1 loss to validate the efficacy of LMP400 and olaparib combination.Results:CellMinerCDB reveals that SLFN11, which kills cells undergoing replicative stress, is a dominant drug determinant to the clinical indenoisoquinolines. In addition, BRCA1-, BRCA2-, and PALB2-deficient cells were hypersensitive to the indenoisoquinolines. All 3 clinical indenoisoquinolines were also synergistic with olaparib, especially in the HRD cells. The synergy between LMP400 and olaparib was confirmed in the orthotopic allograft model harboring BRCA1 loss.Conclusions:Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11.

Topotecan and the indenoisoquinolines TOP1 inhibitors are correlated with response to talazoparib and olaparib in the NCI-60 (panels A-D) and LMP744 is correlated with talazoparib (E), olaparib (F) and cisplatin (G) in the GDSC (MGH-Sanger) cell line panels. However, TOP1 inhibitors remain highly active in many cell lines (colored circles) that do not respond to olaparib, talazoparib or cisplatin. The red lines show the regression lines. The cell lines above the lines (upper left corners) are resistant to the PARP inhibitors but respond to the TOP1 inhibitors. LMP compounds are listed by their NSC numbers in the NCI-60 panels A-D (LMP400 = NSC724998; LMP744 = NSC706744 and LMP776 = NSC725776). LMP744 is also referred as MJ-III-65 in the GDSC (MGH-Sanger) database (panels E-G). Individual plots are snapshots from CellMinerCDB; https://discover.nci.nih.gov/cellminercdb).

Background: Immune thrombocytopenic purpura (ITP) refers to immune-mediated destruction of platelets. Viral infections have been proposed as an etiology of ITP; antibodies developed in response to infection may cross-react with normal platelets and result in their destruction. Case Series: We report 2 cases in which coronavirus disease 2019 (COVID-19) likely induced severe ITP. Conclusion: ITP may also play a role in the thrombocytopenia observed in some patients with COVID-19. ITP in this patient population may be more prevalent than currently documented.

Nongestational choriocarcinoma is a rare malignancy in humans with poor prognosis. Naturally occurring choriocarcinoma is also rare in laboratory mice, and no genetic mouse model accurately recapitulates the features of this cancer. Here we report development of a genetically engineered mouse (GEM) model with alterations in Brca2, Trp53, and RB that develops ovarian tumors. Most of the ovarian tumors displayed histological characteristics of nongestational choriocarcinoma of the ovary (NGCO) (47%) with abundant syncytiotrophoblasts and cytotrophoblasts, positive immunolabeling for human chorionic gonadotropin, and positive periodic acid–Schiff reaction. The rest of the ovarian tumors were serous epithelial ovarian carcinoma (SEOC) (26%) or mixed tumors consisting of NGCO and SEOC (26%). We further established syngeneic orthotopic mouse models for NGCO by in vivo passaging of GEM tumors. These metastatic models provide a platform for evaluating new treatment strategies in preclinical studies aimed at improving outcomes in choriocarcinoma patients.

Purpose: Irinotecan and topotecan are used to treat a variety of different cancers. However, they have limitations, including chemical instability and severe side effects. To overcome these limitations, we developed the clinical indenoisoquinolines: LMP400 (indotecan), LMP776 (indimitecan), and LMP744. The purpose of the study is to build the molecular rationale for phase II clinical trials. Experimental Design: CellMinerCDB (http://discover.nci.nih.gov/cellminercdb) was used to mine the cancer cell lines genomic databases. The causality of Schlafen11 (SLFN11) was validated in isogenic cell lines. Because topoisomerase I (TOP1)-mediated replication DNA damage is repaired by homologous recombination (HR), we tested the “synthetic lethality” of HR-deficient (HRD) cells. Survival and cell-cycle alterations were performed after drug treatments in isogenic DT40, DLD1, and OVCAR cell lines with BRCA1, BRCA2, or PALB2 deficiencies and in organoids cultured from prostate cancer patient-derived xenografts with BRCA2 loss. We also used an ovarian orthotopic allograft model with BRCA1 loss to validate the efficacy of LMP400 and olaparib combination. Results: CellMinerCDB reveals that SLFN11, which kills cells undergoing replicative stress, is a dominant drug determinant to the clinical indenoisoquinolines. In addition, BRCA1-, BRCA2-, and PALB2-deficient cells were hypersensitive to the indenoisoquinolines. All 3 clinical indenoisoquinolines were also synergistic with olaparib, especially in the HRD cells. The synergy between LMP400 and olaparib was confirmed in the orthotopic allograft model harboring BRCA1 loss. Conclusions: Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11.

Camptothecin derivatives topotecan and irinotecan are currently the only FDA-approved topoisomerase I (Top1) inhibitors. Despite their wide usage they have many drawbacks: chemical instability, short half-life, dose-limiting bone marrow and gastrointestinal toxicity, and they are drug efflux substrates. The novel non-camptothecin Top1 inhibitors, indenoisoquinolines (LMP400, LMP776 and LMP744), have been developed to overcome these limitations. We explored whether treatment with LMPs could induce “synthetic lethality” in cells with impaired homologous recombination (HR) repair mechanism and whether it could be enhanced by combining them with PARP inhibitor, olaparib. Using the DT40 cell line, we assessed in vitro the role of HR in the cellular responses to the LMPs. We found that BRCA1-, BRCA2- and PALB2-deficient cells are 3 to 5 times more sensitive to the LMP compounds than wild type cells. Moreover, combination treatments showed a significant synergy between each of the three LMPs and olaparib. To confirm the differential response of Brca1 wild type or Brca1 deficient cells to LMP treatment we assessed compound potency in primary ovarian cancer cell lines derived from a genetically engineered mouse (GEM) model for serous epithelial ovarian cancer (SEOC). As in DT40 cells, we observed that murine Brca1 deficient cells were more sensitive to all 3 LMP compounds than Brca1 wild type cells. Our results suggest that Brca1 deficiency renders cells more sensitive to treatment with LMPs or combination of LMPs and olaparib, potentially directing selection of patients with impaired HR repair mechanism in the phase 2 clinical trials that are in preparation. To confirm this observation in vivo, we are performing efficacy studies using LMP compounds alone or in combination with olaparib in orthotopic allograft mouse models for ovarian cancer derived from the GEM model. In Brca1 deficient tumors, treatment with each of the 3 LMP compounds led to significant increase of survival compared to vehicle treated group. LMP400 had the greatest beneficial impact on survival and tumor regression. To confirm synergy between LMPs and olaparib we selected LMP400 to represent the LMPs and repeated the efficacy study using Brca1 deficient tumor model. We observed that suboptimal doses of LMP400 or olaparib used as single treatments resulted in some increase in survival, however, when combined they significantly increased survival due to tumor regression. Our data demonstrate that the LMPs synergize with olaparib and provide a rationale for personalized treatment and Phase 2 clinical trials with the indenoisoquinolines in combination with PARP inhibitors in HR-deficient ovarian cancers. Citation Format: Ludmila Szabova, Melanie Gordon, Laetitia Matzi, Yves Pommier, Zoe Weaver Ohler. EFFICACY OF NOVEL TOPOISOMERASE 1 INHIBITORS AND THEIR SYNERGY WITH PARP INHIBITORS IN A MURINE MODEL FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-110.

The alarming obesity prevalence in Black women is well documented yet poorly understood. Obesity interventions for Black women have failed to produce long-term reductions in weight. Recommendations to incorporate a lifestyle and behavioral modification approach have been made to address obesity in this population. The purpose of this article was to provide a comprehensive review of the literature to identify lifestyle and behavioral modification obesity intervention studies for Black women. We included articles published between February 1992 and January 2013. This search identified 28 articles from the PsycInfo, MEDLINE, CINAHL, and SPORTDiscus databases. Results of these studies were summarized primarily into six categories. The importance of modest improvements in health outcomes that result from adapting healthier behaviors was highlighted. Future research is required for identifying the most salient intervention component or combination of components that lead to the best outcomes for ensuring intervention success and minimizing weight regain postintervention.

With the end of the Spanish Civil War in the spring of 1939 and the outbreak of the Second World War the following September, the nation that many antifascist Germans identified as their ideological utopia — France — turned against them. After France's declaration of war on Germany in September 1939, all Germans living in France became `enemies of the French state' and were forced to report to internment camps. Drawing on a variety of archival and published documents — poems, plays, novels, personal memoirs, posters and camp reports — produced by German antifascists who were interned in French internment camps in 1939—40, this study examines how imprisonment in France affected the German antifascist concept of France and the political ideals it represented.

Purpose: Because publicly-funded, community-based physical therapy (PT) services through Ontario's network of Schedule 5 providers were partially delisted in April 2005, we examined the perceived consequences of this policy decision among different provider categories following partial delisting. Schedule 5 providers or clinics, renamed “Designated Physiotherapy Clinics” following partial delisting, are privately-owned and operated facilities that have agreements with Ontario's Ministry of Health and Long-Term Care to deliver publicly funded services for eligible clients. Methods: A health policy research approach used semi-structured telephone interviews with 33 physical therapists from Schedule 5 clinics, home care settings, hospitals, and private clinics within the Greater Toronto Area and across Ontario. Results: Schedule 5 providers perceived an immediate decrease in demand, whereas PT providers from other categories reported no change at the time of interview. Conversely, all providers forecasted decreased access for ineligible clients but a potential for improved access and reduced wait times among those who remained eligible. In the final analysis, PT informants in all categories agreed that partial delisting was an improved policy decision compared with full delisting, as proposed initially. Conclusions: Perceived consequences appeared to depend on provider type. However, informants from all provider categories cautioned that this policy decision would have a significant impact on the health status of some Ontarians. Further research is warranted to explore the long-term effects of this policy decision.

The Institute of Medicine (IOM) defines healthcare disparities as “racial or ethnic differences in the quality of health care that are not due to access-related factors or clinical needs, preferences, and appropriateness of intervention.”1 The IOM’s recent report “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care”1 highlighted health-care disparities across an array of acute and chronic disease conditions,1–7 even after accounting for socioeconomic status (SES), insurance coverage, age, and comorbidities.1,8 The identification of minority health disparities, including migraine, is a priority of the National Institutes of Health (NIH)9 and at the National Institute of Neurological Disorders and Stroke within NIH.10 Research into potential ethnic disparities in pain management have consistently found evidence of disparities in acute pain, cancer pain, and chronic pain.11–16 For example, non-Caucasians are less likely than Caucasians to be prescribed analgesics.14–16 Little research has investigated potential disparities in migraine care. More Caucasians (20%) than African Americans (16%) have migraines;17 this is likely due to variations in genetic vulnerability.17 Thus, one would expect ethnic differences in health-care utilization for migraine care. However, an analysis of National Hospital Ambulatory Health Care Survey data found that 91% of those presenting for care were Caucasians compared to 6% African Americans.18 After accounting for population and migraine prevalence group differences, African Americans were 67% less likely to present for care than would be expected. This suggests a disparity in utilizing care. One common rationale given for differences in utilization rates is access to care.8,19,20 However, there are examples of disease entities where different ethnic groups with the same access to care differ in utilizing the health-care system.21,22 One way to correct this is to compare individuals with similar access to health care. In addition to utilization, it is important to consider whether ethnic differences exist for managing migraine. A recent study found that African Americans, Hispanics, and Caucasians responded similarly to triptans.23 Thus, one would expect treatment regimens (eg, prescribing migraine-specific medications or migraine preventive medications as appropriate) to be similar. However, an observation of ethnic differences in treatment regimens would not necessarily imply intention on the part of the physician or the health-care system. It is possible that patient–physician communication (PPC) and/or level of trust influences the care individuals receive. It appears that ethnic minorities are more skeptical of the health-care system1,24,25 and have a more negative view of perception of PPC.26 Transparent, trusting communication is essential for efficacious disease management. This need is heightened in migraine and other pain disorders where there is no viable external measure (eg, MRI, blood test) available to establish the presence or severity of pain that is more reliable or valid than the patient’s report to their physician. Any breakdown in PPC will negatively impact treatment quality in pain disorders. Thus, when evaluating potential ethnic disparities in migraine care, it is important to assess not only whether migraineurs of different ethnicities access and receive equitable care, but also whether they have similar perceptions of trust and communication regarding their health-care provider. It has been proposed by some that disparities are a simple result of environmental or genetic differences. For example, SES (commonly associated with income, education, or employment) contributes to healthcare disparities.1,27–29 However, ethnic health-care disparities exist even after controlling for SES.24,29 Others have suggested that disparities in prescriptions of pain medication are due to ethnic differences in pain perception and need for pain medication. However, in pain patients who are able to control the amount of medication they receive, there are no ethnic differences.16 The purpose of the current study was to evaluate whether Caucasians and African Americans with moderately to severely disabling migraines differed in regards to: (a) utilization of the health-care system for headache treatment; (b) physician-guided diagnosis and treatment for migraine; (c) mistrust in the healthcare system and perceived communication with their physician; and (d) perceived headache triggers. The local Institutional Review Board approved the protocol for the current study.