Impact of balance on the energetic cost of walking and gait speed.

BACKGROUND: Examine the relationship between balance test performance and the energetic cost of walking (ECW) and gait speed. METHODS: Cross-sectional and longitudinal analyses of data from the Baltimore Longitudinal Study of Aging. Men (48%) and women aged 60-96 years enrolled in the BLSA between 2007 and 2020 (n = 1132). Balance was assessed using narrow walk (NW) and progressive standing balance tests (SB). ECW measured during 2.5-min usual paced walk while participants wore a portable indirect calorimeter. Gait speed assessed over 6-m. Each test parameterized using validated methods. Statistical analysis to compare balance measures to ECW, and gait speed used generalized logistic regression models and adjustments for age, sex, race, height, weight, and comorbidities. RESULTS: Cross-sectionally, mean ECW was higher and gait speed slower in persons who failed the NW than those who passed (0.189 vs. 0.164 mL/kg/m, p < 0.0001 and 0.96 vs. 1.15 m/s, p < 0.0001, respectively). Mean ECW was increasingly higher and gait speed slower over three progressively challenging SB tests (0.207 vs. 0.171 vs. 0.164 mL/kg/m, p < 0.0001 and 0.95 vs. 1.05 vs. 1.15 m/s, p < 0.0001). Over an average 2.4 years, those who declined in SB and NW had a higher ECW and slower gait speed than persons who maintained performance (SB: 0.18 vs. 0.160 mL/kg/m, p = 0.0003, and 1.00 vs. 1.13 m/s, p = <0.001; NW: 0.175 vs. 0.160 mL/kg/m, p = 0.002, and 1.04 vs. 1.14 m/s, p = 0.001). Persons who improved had lower ECW and faster gait speed than those who failed at both visits (SB: 0.169 vs. 0.240 mL/kg/m, p = 0.0002, and 0.99 vs. 0.94 m/s, p = 0.67, NW: 0.163 vs. 0.195 mL/kg/m, p = 0.0005, and 1.10 vs. 0.92 m/s, p < 0.001). CONCLUSION: Instability contributes to higher ECW and slower gait speed which suggests that rehabilitation efforts to improve balance may help maintain function further into older adulthood and delay mobility limitation.

Perceived sleep quality predicts aggressive offending in adolescence and young adulthood.

BACKGROUND: There are profound consequences when developing youth do not get adequate sleep. Adolescents who experience poor sleep may be more likely to engage in offending behavior. While there is a documented association between the number of hours youth sleep and their likelihood of offending, it is unclear how youths' perceptions of their sleep quality contribute to offending. Further, scholars have yet to rigorously examine the relation between sleep problems and offending in young adulthood, a developmental stage, which is both critical for desistance and in which sleep may play an important role. METHODS: Using a sample of 1,216 justice-involved male youth, this study uses within-individual longitudinal methods (fixed-effects Poisson regression models) to examine the relation between changes in perceptions of sleep quality and changes in offending behavior from ages 13 to 24. RESULTS: Increases in sleep problems are associated with increases in offending, particularly aggressive/person-related offenses, for both adolescents and young adults. This holds true even after controlling for time-varying anxiety, substance use, and violence exposure. CONCLUSIONS: Improving sleep quality may be critical for reducing aggressive behavior in at-risk adolescents and young adults. Interventions that address sleep quality, and not just quantity, may be particularly beneficial.

Use of a Novel Trigger Tool to Identify Palliative Care Needs in Surgical Patients at a National Referral Hospital in Kenya: A Pilot Study.

Background: Addressing unmet palliative care needs in high-risk surgical patients in low- and middle-income countries must include innovative approaches to limitations in personnel and culturally acceptable assessment modalities. Objectives: We assessed the utility of a novel seven-item "Step-1" trigger tool in identifying surgical patients who may benefit from palliative care. Design: All adult patients (≥18 years) on general surgery, neurosurgery, and orthopedic surgery wards were enrolled over a four-month period. Setting/Subjects: This study took place at Moi Teaching and Referral Hospital (MTRH), one of two Kenyan national referral hospitals. Measurements: The "Step-1" trigger tool was administered, capturing provider estimates of prognosis, cancer history, social barriers, admission frequency, hospice history, symptom burden, and functional decline/wasting. A cut-point of ≥3 positive factors was selected, indicating a patient may benefit from palliative care. Results: A total of 411 patients were included for analysis. Twenty-five percent (n = 102) of patients had scores ≥3. The cut-point of ≥3 was significantly associated with identifying high-risk patients (HRP; χ2 = 32.3, p < 0.01), defined as those who died or were palliatively discharged, with a sensitivity and specificity of 63.9% and 78.9%, respectively. Survey questions with the highest overall impact included: "Would you be not surprised if the patient died within 12 months?," "Are there uncontrolled symptoms?," and "Is there functional decline/wasting?" Conclusions: This pilot study demonstrates that the "Step-One" trigger tool is a simple and effective method to identify HRP in resource-limited settings. Although this study identified three highly effective questions, the seven-question assessment is flexible and can be adapted to different settings.

Tracing nutrient pollution from industrialized animal production in a large coastal watershed.

One of the highest concentrations of swine and poultry concentrated animal feeding operations (CAFOs) in North America is located on the Coastal Plain of North Carolina, in which the Cape Fear River basin is located. The CAFOs produce vast amounts of manure causing loading of nutrients and other pollutants to receiving waters. With the Cape Fear River basin vulnerable to nutrient pollution, as are many other watersheds with CAFOs, δ13C and δ15N stable isotopic signatures were identified from water samples collected within the Northeast Cape Fear, Black, and lower Cape Fear River watersheds to trace nutrient sources and their distribution downstream. The spatial and temporal variability of nutrients and isotopic signatures were also identified to understand water quality impacts of animal waste spraying season and proximity to CAFOs. Our results showed that significantly enriched δ15N signatures characterized sites in close proximity to CAFOs as well as point-source wastewater discharge areas, while the opposite was true for an unimpacted control stream and two estuarine sites. Additionally, the impacted sites yielded significantly (p < 0.05) higher nitrate concentrations than control and estuarine sites. Statistical analyses demonstrated that nitrate concentrations were positively correlated with heavier δ15N signatures, suggesting that animal waste, as well as human wastewater, are relatively more important sources of N to this large watershed than fertilizers from traditional row crop agriculture. Our results also suggested that during appropriate hydrological conditions CAFO-derived N can be detected many kilometers downstream from freshwater sources areas to the estuary.

DO POSITIVE PERCEPTIONS OF CORRECTIONAL STAFF MITIGATE INSTITUTIONAL VIOLENCE AMONG YOUTHFUL OFFENDERS?

Juvenile justice facilities can be dangerous places for adolescents and may promote violent behavior among incarcerated youth. With high rates of violence among detained juveniles, youth who do not feel safe may resort to violent behavior to protect themselves. However, this "cycle of violence" may be interrupted if youth can turn to correctional staff for support. Using a 3-wave, longitudinal sample of 373 male incarcerated adolescents, the results indicated that as compared to violence exposure prior to incarceration, exposure to institutional violence more strongly predicts violent behavior. Further, the findings indicated that perceptions of staff serve as a buffer to violence exposure and may interrupt the cycle of violence. Policy implications are discussed.

Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.

Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab.

4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T cells. Clinical trials of two agonist antibodies, utomilumab (PF-05082566) and urelumab (BMS-663513), are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic. To understand these differences, we solved structures of the human 4-1BB/4-1BBL complex, the 4-1BBL trimer alone, and 4-1BB bound to utomilumab or urelumab. The 4-1BB/4-1BBL complex displays a unique interaction between receptor and ligand when compared with other TNF family members. Furthermore, our ligand-only structure differs from previously published data. Utomilumab, a ligand-blocking antibody, binds 4-1BB between CRDs 3 and 4. In contrast, urelumab binds 4-1BB CRD-1, away from the ligand binding site. Finally, cell-based assays demonstrate utomilumab is a milder agonist than urelumab. Collectively, our data provide a deeper understanding of the 4-1BB signaling complex, providing a template for future development of next generation 4-1BB targeted biologics.

My Hypertension Education and Reaching Target (MyHEART): Development and Dissemination of a Patient-Centered Website for Young Adults with Hypertension.

BACKGROUND: Young adults (18 to 39 years old) with hypertension have the lowest rates of blood pressure control (defined as blood pressure less than 140/90 mmHg) compared to other adult age groups. Approximately 1 in 15 young adults have high blood pressure, increasing their risk of future heart attack, stroke, congestive heart failure, and/or chronic kidney disease. Many young adults reported having few resources to address their needs for health education on managing cardiovascular risk. OBJECTIVE: The goal of our study was to develop and disseminate a website with evidence-based, clinical information and health behavior resources tailored to young adults with hypertension. METHODS: In collaboration with young adults, health systems, and community stakeholders, the My Hypertension Education and Reaching Target (MyHEART) website was created. A toolkit was also developed for clinicians and healthcare systems to disseminate the website within their organizations. The dissemination plan was guided by the Dissemination Planning Tool of the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Google Analytics data were acquired for January 1, 2017 to June 29, 2017. The MyHEART website received 1090 visits with 2130 page views; 18.99% (207/1090) were returning visitors. The majority (55.96%, 610/1090) approached the website through organic searches, 34.95% (381/1090) accessed the MyHEART website directly, and 5.96% (65/1090) approached through referrals from other sites. There was a spike in site visits around times of increased efforts to disseminate the website. CONCLUSIONS: The successfully implemented MyHEART website and toolkit reflect collaborative input from community and healthcare stakeholders to provide evidence-based, portable hypertension education to a hard-to-reach population. The MyHEART website and toolkit can support healthcare providers' education and counseling with young adults and organizations' hypertension population health goals.

A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies.

The chemokine receptor CXCR4 is highly expressed and associated with poor prognosis in multiple malignancies. Upon engagement by its ligand, CXCL12, CXCR4 triggers intracellular signaling pathways that control trafficking of cells to tissues where the ligand is expressed, such as the bone marrow (BM). In hematologic cancers, CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism driving disease and therapy resistance. We developed a humanized CXCR4 immunoglobulin G1 (IgG1) antibody (Ab), PF-06747143, which binds to CXCR4 and inhibits CXCL12-mediated signaling pathways, as well as cell migration. In in vivo preclinical studies, PF-06747143 monotherapy rapidly and transiently mobilized cells from the BM into the peripheral blood. In addition, PF-06747143 effectively induced tumor cell death via its Fc constant region-mediated effector function. This Fc-mediated cell killing mechanism not only enhanced antitumor efficacy, but also played a role in reducing the duration of cell mobilization, when compared with an IgG4 version of the Ab, which does not have Fc-effector function. PF-06747143 treatment showed strong antitumor effect in multiple hematologic tumor models including non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM). Importantly, PF-06747143 synergized with standard-of-care agents in a chemoresistant AML patient-derived xenograft model and in an MM model. These findings suggest that PF-06747143 is a potential best-in-class anti-CXCR4 antagonist for the treatment of hematologic malignancies, including in the resistant setting. PF-06747143 is currently in phase 1 clinical trial evaluation (registered at www.clinicaltrials.gov as #NCT02954653).

Modulation of P2X3 and P2X2/3 Receptors by Monoclonal Antibodies.

Purinergic homomeric P2X3 and heteromeric P2X2/3 receptors are ligand-gated cation channels activated by ATP. Both receptors are predominantly expressed in nociceptive sensory neurons, and an increase in extracellular ATP concentration under pathological conditions, such as tissue damage or visceral distension, induces channel opening, membrane depolarization, and initiation of pain signaling. Hence, these receptors are considered important therapeutic targets for pain management, and development of selective antagonists is currently progressing. To advance the search for novel analgesics, we have generated a panel of monoclonal antibodies directed against human P2X3 (hP2X3). We have found that these antibodies produce distinct functional effects, depending on the homomeric or heteromeric composition of the target, its kinetic state, and the duration of antibody exposure. The most potent antibody, 12D4, showed an estimated IC50 of 16 nm on hP2X3 after short term exposure (up to 18 min), binding to the inactivated state of the channel to inhibit activity. By contrast, with the same short term application, 12D4 potentiated the slow inactivating current mediated by the heteromeric hP2X2/3 channel. Extending the duration of exposure to ∼20 h resulted in a profound inhibition of both homomeric hP2X3 and heteromeric hP2X2/3 receptors, an effect mediated by efficient antibody-induced internalization of the channel from the plasma membrane. The therapeutic potential of mAb12D4 was assessed in the formalin, complete Freund's adjuvant, and visceral pain models. The efficacy of 12D4 in the visceral hypersensitivity model indicates that antibodies against P2X3 may have therapeutic potential in visceral pain indications.

Integration of Palliative Care Into Comprehensive Cancer Treatment at Moi Teaching and Referral Hospital in Western Kenya.

PURPOSE: The prognosis for the majority of patients with cancer in Kenya is poor, with most patients presenting with advanced disease. In addition, many patients are unable to afford the optimal therapies required. Therefore, palliative care is an essential part of comprehensive cancer care. This study reviews the implementation of a palliative care service based at the Moi Teaching and Referral Hospital in Eldoret, Kenya, and describes the current scope and challenges of providing palliative care services in an East African tertiary public referral hospital. METHODS: This is a review of the palliative care clinical services at the only tertiary public referral hospital in western Kenya from January 2012 through September 2014. Palliative care team members documented each patient's encounter on standardized palliative care assessment forms; data were then entered into the Academic Model Providing Access to Health Care (AMPATH)-Oncology database. Interviews were also conducted to identify current challenges and opportunities for program improvement. RESULTS: This study documents the implementation of a palliative care service line in Eldoret, Kenya. Barriers to providing optimal palliative cancer care include distance to pharmacies that stock opioids, limited selection of opioid preparations, education of health care workers in palliative care, access to palliative chemoradiation, and limited availability of outpatient and inpatient hospice services. CONCLUSION: Palliative care services in Eldoret, Kenya, have become a key component of its comprehensive cancer treatment program.

Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

Genetic variation in the IL-7 receptor-α (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ-producing CD4(+) (T(H)1) and IFN-γ-producing CD8(+) T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.

Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9.

Target-mediated clearance and high antigen load can hamper the efficacy and dosage of many antibodies. We show for the first time that the mouse, cynomolgus, and human cross-reactive, antagonistic anti-proprotein convertase substilisin kexin type 9 (PCSK9) antibodies J10 and the affinity-matured and humanized J16 exhibit target-mediated clearance, resulting in dose-dependent pharmacokinetic profiles. These antibodies prevent the degradation of low density lipoprotein receptor, thus lowering serum levels of LDL-cholesterol and potently reducing serum cholesterol in mice, and selectively reduce LDL-cholesterol in cynomolgus monkeys. In order to increase the pharmacokinetic and efficacy of this promising therapeutic for hypercholesterolemia, we engineered pH-sensitive binding to mouse, cynomolgus, and human PCSK9 into J16, resulting in J17. This antibody shows prolonged half-life and increased duration of cholesterol lowering in two species in vivo by binding to endogenous PCSK9 in mice and cynomolgus monkeys, respectively. The proposed mechanism of this pH-sensitive antibody is that it binds with high affinity to PCSK9 in the plasma at pH 7.4, whereas the antibody-antigen complex dissociates at the endosomal pH of 5.5-6.0 in order to escape from target-mediated degradation. Additionally, this enables the antibody to bind to another PCSK9 and therefore increase the antigen-binding cycles. Furthermore, we show that this effect is dependent on the neonatal Fc receptor, which rescues the dissociated antibody in the endosome from degradation. Engineered pH-sensitive antibodies may enable less frequent or lower dosing of antibodies hampered by target-mediated clearance and high antigen load.

Implications of hypertrophic cardiomyopathy transmitted by sperm donation.

CONTEXT: Sperm donation is an increasingly common practice for achieving pregnancy in the absence of a male partner or when fertility is problematic. The unintended consequence in which genetic diseases are unwittingly transmitted to offspring is an underrecognized public health issue not previously prioritized by US Food and Drug Administration guidelines. OBJECTIVE: To report the clinical circumstances and implication of hypertrophic cardiomyopathy (HCM) transmitted by sperm donation to recipients. SETTING: Voluntary sperm donation through a US Food and Drug Administration-approved tissue bank. MAIN OUTCOME MEASURE: Incidence of genetically affected offspring and clinical outcomes to date. RESULTS: An asymptomatic 23-year-old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel beta-myosin heavy-chain mutation that caused HCM, after an offspring was clinically diagnosed with this disease. Of the 24 children known to be offspring of the donor, including 22 who were products of fertilization via sperm donation and 2 conceived by the donor's wife, a total of 9 genetically affected offspring, 2 to 16 years of age and 6 males, have been identified with HCM (2005-2009). Three of the 9 gene-positive children have currently expressed phenotypic evidence of HCM, including one who died at age 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at age 15 years. The latter 2 children and the donor are judged likely to be at increased risk for sudden death. CONCLUSIONS: This case series underscores the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (eg, HCM) such as consideration for 12-lead electrocardiograms.

A new era in clinical genetic testing for hypertrophic cardiomyopathy.

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

The ACTCellerate initiative: large-scale combinatorial cloning of novel human embryonic stem cell derivatives.

Human embryonic stem cells offer a scalable and renewable source of all somatic cell types. Human embryonic progenitor (hEP) cells are partially differentiated endodermal, mesodermal and ectodermal cell types that have not undergone terminal differentiation and express an embryonic pattern of gene expression. Here, we describe a large-scale and reproducible method of isolating a diverse library of clonally purified hEP cell lines, many of which are capable of extended propagation in vitro. Initial microarray and non-negative matrix factorization gene-expression profiling suggests that the library consists of at least 140 distinct clones and contains many previously uncharacterized cell types derived from all germ layers that display diverse embryo- and site-specific homeobox gene expression. Despite the expression of many oncofetal genes, none of the hEP cell lines tested led to tumor formation when transplanted into immunocompromised mice. All hEP lines studied appear to have a finite replicative lifespan but have longer telomeres than most fetal- or adult-derived cells, thereby facilitating their use in the manufacture of purified lineages for research and human therapy.

Modulation of the G2 cell cycle checkpoint by sesquiterpene lactones psilostachyins A and C isolated from the common ragweed Ambrosia artemisiifolia.

A phenotypic cell-based assay for inhibitors of the G (2) DNA damage checkpoint was used to screen plant extracts from the US National Cancer Institute Natural Products Repository. It revealed activity in a methanol extract from the common ragweed Ambrosia artemisiifolia. Assay-guided fractionation led to the identification of the sesquiterpene lactones psilostachyins A and C as novel checkpoint inhibitors. Elimination of their alpha,beta-unsaturated carbonyl group caused a loss of activity, suggesting that the compounds can bind covalently to target proteins through Michael addition. Psilostachyins A and C also blocked cells in mitosis and caused the formation of aberrant microtubule spindles. However, the compounds did not interfere with microtubule polymerization in vitro. The related sesquiterpene lactones psilostachyin B, paulitin and isopaulitin were also isolated from the same extract but showed no checkpoint inhibition. The identification of the target(s) of psilostachyins A and C may provide further insight into the signalling pathways involved in cell cycle arrest and mitotic progression.

New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis.

Inhibitors of the G2 DNA damage checkpoint can selectively sensitize cancer cells with impaired p53 tumor suppressor activity to killing by DNA-damaging drugs or ionizing radiation and have been proposed as a promising therapeutic strategy. An extract from the Northeastern Pacific marine sponge Merriamum oxeato showed G2 checkpoint inhibitory activity, and fractionation identified the known dinoflagellate toxin dinophysistoxin 1 (1) and the two novel analogues 27-O-acetylokadaic acid (2) and 27-O-acetyldinophysistoxin 1 (3) as the active compounds. The mixture of 1, 2, and 3 was extremely potent at inhibiting the G2 checkpoint (IC(50) = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC(50) = 1 ng/mL), and it radiosensitized MCF-7 breast cancer cells expressing mutated p53 at all concentrations tested. However, the mixture of 1, 2, and 3 was also very toxic to cells not exposed to DNA damage (IC(50) = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.