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Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder11Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 2IDEXX BioAnalytics, Columbia, MO, USA; 3Department of Biology, Washburn University, Topeka, KS, USA; 4Department of Nutrition and Exercise Physiology and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 5Hamon Center for Therapeutic Oncology Research and Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USABackground: Approximately 15–20% of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80% of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis.Methods: APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models.Results: APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone.Conclusion: Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.Keywords: breast cancer, metastasis, blood-vessel targeting agent, p53, APR-246

تسعى هذه المحاولة البحثية إلى إعادة تقييم للرواية الرسمية والنموذج التفسيري الذي انتجته محاكمات نورمبيرغ بشان الابادة النازية لليهود، والتحقق من مديات المطابقة بين هذه الادعاءات وبين الواقع التاريخي الفعلي للسياسات النازية ازاءهم، عن طريق تقديم قراءة لوظيفة معسكرات الاعتقال وعلاقتها ببرنامج " الابادة " المفترض والذي أطلق عليه " الحل النهائي، في سنوات الحرب العالمية الثانية. قسم البحث إلى ثلاث موضوعات الأول " مقدمات التوظيف الاقتصادي لمعسكرات الاعتقال " أما الثاني فقد كرس لبحث وظيفة المعسكرات في ضوء برنامج العمل القسري " معسكرات العمل القسري في ضوء متطلبات النظام النازي الاقتصادية 1939-1941". في حين ناقش الثالث إشكالية اقتران المعسكرات بالإبادة لذا جاء بعنوان " معسكرات " الابادة " اشكالية التوصيف والوظيفة المفترضة".

Yayun Liang,1 Benford Mafuvadze,1 Cynthia Besch-Williford,2 Salman M Hyder1 1Deparment of Biomedical Sciences and Dalton Cardiovascular Research Center, Columbia, MO, USA; 2IDEXX BioResearch, Columbia, MO, USA Background: Between 30 and 40% of human breast cancers express a defective tumor suppressor p53 gene. Wild-type p53 tumor suppressor protein promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor–dependent angiogenesis, whereas mutant p53 protein (mtp53) lacks these functions, resulting in tumor cell survival and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for combating mtp53-expressing breast cancer. Methods: In this study, we sought to determine whether administration of APR-246, a small-molecule drug that restores p53 function, in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits advanced hormone-dependent breast cancer tumor growth. Results: APR-246 reduced cell viability in mtp53-expressing BT-474 and T47-D human breast cancer cells in vitro, and significantly induced apoptosis in a dose-dependent manner. However, APR-246 did not reduce cell viability in MCF-7 breast cancer cells, which express wild-type p53. We next examined APR-246’s anti-tumor effects in vivo using BT-474 and T47-D tumor xenografts established in female nude mice. Tumor-bearing mice were treated with APR-246 and/or 2aG4 and tumor volume followed over time. Tumor growth was more effectively suppressed by combination treatment than by either agent alone, and combination therapy completely eradicated some tumors. Immunohistochemistry analysis of tumor tissue sections demonstrated that combination therapy more effectively induced apoptosis and reduced cell proliferation in tumor xenografts than either agent alone. Importantly, combination therapy dramatically reduced the density of blood vessels, which serve as the major route for tumor metastasis, in tumor xenografts compared with either agent alone. Conclusion: Based on our findings, we contend that breast tumor growth might effectively be controlled by simultaneous targeting of mtp53 protein and tumor blood vessels in mtp53-expressing cancers. Keywords: breast cancer, blood vessel targeting agent, p53, APR-246, apoptosis, angiogenesis

Background. Iron-deficiency anemia is widespread among young children in the Kyrgyz Republic, and there is an urgent need to identify an effective intervention to address this significant public health problem. Objective. To test the effectiveness of a 2-month intervention with daily homefortification of complementary food using micronutrient powder (Sprinkles) in reducing anemia among children 6 to 36 months of age in the Kyrgyz Republic. Methods. In this cluster-randomized, communitybased effectiveness trial conducted in three regions of the Kyrgyz Republic, 24 clusters of children aged 6 to 36 months were randomly assigned to two groups. The intervention group (12 clusters, n = 1,103) received 60 sachets of micronutrient powder (12.5 mg elemental iron), which were taken as one sachet daily for 2 months. The control group (12 clusters, n = 1,090) did not receive micronutrient powder until after the study period. Blood hemoglobin concentration was assessed at the start and end of the intervention. Results. From baseline to follow-up, the mean hemoglobin concentration in the intervention group increased by 7 gIL, whereas it decreased by 2 gIL in the control group (p < .001). The prevalence of anemia (hemoglobin <110 gIL) in the intervention group decreasedfrom 72% at baseline to 52% atfollow-up, whereas it increasedfrom 72% to 75% in the control group (p < .001). Compliance with the intervention was high, with children consuming on average 45 of the 60 sachets given. Conclusions. A course of 60 Sprinkles micronutrient powder sachets taken daily for 2 months is effective in improving hemoglobin levels and reducing the prevalence of anemia among young children in the Kyrgyz Republic. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence of anaemia and maternal and infant factors associated with Hb values in infants at 6 months of age in rural Bangladesh. Design: Infants (born to mothers supplemented with Fe-folic acid from midpregnancy) were visited at birth and 6 months of age. Mothers' anthropometric status, and infants' birth weight, gestational age at birth, weight and Hb concentration at 6 months were measured. Household socio-economic and demographic data, infant feeding practices and health status were collected using a pre-tested structured questionnaire. Setting: Rural Bangladesh. Subjects: Four hundred and two infants. Results: For the total cohort (n 402), the range of anaemia prevalence values was from 30·6% using a cut-off value of Hb<95 g/l to 71·9% using a value of Hb<110 g/l. Birth weight and month of birth were the only factors positively associated with infant Hb in a linear regression model (P=0·008 and 0·011, respectively). Conclusions: There was an unexpectedly high prevalence of anaemia in infants at 6 months of age, before the assumed period of vulnerability. Hb at this age tended to be higher in those with higher birth weight. We also found a season effect on Hb, as it tended to be higher as the study progressed. The high prevalence of anaemia at such an early age needs to be addressed to minimize the disease's long-term consequences. [ABSTRACT FROM AUTHOR]

Background. The effectiveness of commonly suggested public health interventions to control childhood iron-deficiency anemia has been low. Objective. To determine whether iron provided in Sprinkles daily or in a higher dose once weekly affected hemoglobin, serum ferritin levels, and serum transferrin receptor levels, and to determine whether there were differences in the effects of the two regimens. Methods. In this cluster-randomized, community-based trial conducted in rural areas of Bangladesh, 136 children aged 12 to 24 months with mild to moderate anemia (hemoglobin 70-109 g/L) were randomly allocated to receive Sprinkles daily (12.5 mg of elemental iron, n = 79) or once weekly (30 mg of elemental iron, n = 73) for 8 weeks. Hemoglobin, serum ferritin, and serum transferrin receptor were assessed at the start and end of the intervention. Results. In both groups, there were significant increases in hemoglobin and serum ferritin and a significant decrease in serum transferrin receptor (p <). There were no significant differences between the groups in the increases in hemoglobin (16.1 ± 13.2 g/L for the group receiving Sprinkles daily and 12.3 ± 13.3 g/L for the group receiving Sprinkles once weekly) and serum ferritin (10.6 and 5.7 µg/L, respectively). The decrease in serum transferrin receptor also did not significantly differ between the groups (median, -2.5 and -1. 8 mg/L, respectively). The prevalence rates of iron-deficiency anemia, depleted iron stores, and tissue iron deficiency decreased significantly within each group (p < .01), with no significant differences between the groups. Conclusions. Home fortification of complementary foods with Sprinkles given either daily or once weekly improved iron-deficiency anemia and iron status among young children. [ABSTRACT FROM AUTHOR]