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Abstract Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cells in vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice. In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression. In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), including SLUG, SNAIL, VIMENTIN, and E-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.

PURPOSE: To evaluate the results of an intensive polychemotherapy regimen for Burkitt lymphoma (BL) in sub-Saharan African pediatric centers. PATIENTS AND METHODS: Children with advanced-stage BL (stages II bulky, III, and IV) treated with the GFAOP–Lymphomes Malins B (GFALMB) 2009 protocol in 7 centers between April 2009 and September 2015 were prospectively registered. Treatment regimen contained a prephase with cyclophosphamide followed by 2 induction courses (cyclophosphamide, vincristine, prednisone, high-dose methotrexate [HDMTX]), 2 consolidation courses (cytarabine, HDMTX), and a maintenance phase only for stage IV. HDMTX was given at the dose of 3 g/m2. RESULTS: Four hundred patients were analyzed: 7% had stage II bulky, 76% stage III, and 17% stage IV disease. Median age was 7.3 years, and sex ratio was 1.9:1 (male:female). A total of 221 patients received the whole protocol treatment and 195 achieved complete remission (CR), 11 of them after a second-line treatment. Treatment abandonment rate was 22%. One hundred twenty-five patients died, of whom 49 deaths were related to treatment toxicity. A total of 275 patients are alive, including 25 despite treatment abandonment, but only 110 are known to be in CR with a follow-up > 1 year, indicating a high rate of loss to follow-up. Twelve-month overall survival (OS) was 60% (95% CI, 54% to 66%) and 63%, 60%, and 31%, respectively, for stage II bulky, III, and IV. Patients with stage III disease who started second induction course within 34 days had OS of 76%, versus 57% (P = .0062) beyond 34 days. CONCLUSION: The GFA-LMB2009 protocol improved patients’ survival. Early dose intensity of treatment is a strong prognostic factor. Improving supportive care and decreasing loss to follow-up are crucial.

PURPOSE: Multidisciplinary management of Wilms tumor has been defined through multicenter prospective studies and an average expected patient cure rate of 90%. In sub-Saharan Africa, such studies are uncommon. After the encouraging results of the first Groupe Franco-Africain d'Oncologie Pédiatrique (GFAOP) study, we report the results of the GFAOP-NEPHRO-02 study using an adaptation of the International Society of Paediatric Oncology 2001 protocol. PATIENTS AND METHODS: From April 1, 2005, to March 31, 2011, seven African units participated in a nonrandomized prospective study. All patients who were referred with a clinical and radiologic diagnosis of renal tumor were screened. Those older than age 6 months and younger than 18 years with a unilateral tumor previously untreated were pre-included and received preoperative chemotherapy. Patients with unfavorable histology or with a tumor other than Wilms, or with a nonresponding stage IV tumor were excluded secondarily. RESULTS: Three hundred thirteen patients were initially screened. Two hundred fifty-seven patients were pre-included and 169 with histologic confirmation of intermediate-risk nephroblastoma were registered in the study and administered postoperative treatment. Thirty-one percent of patients were classified as stage I, 38% stage II, 24% stage III, and 7% stage IV. Radiotherapy was not available for any stage III patients. Three-year overall survival rate was 72% for all study patients and 73% for those with localized disease. CONCLUSION: It was possible to conduct sub-Saharan African multicenter therapeutic studies within the framework of GFAOP. Survival results were satisfactory. Improvements in procedure, data collection, and outcome are expected in a new study. Radiotherapy is needed to reduce the relapse rate in patients with stage III disease.

Overexpression of chemokine receptor type 4 (CXCR4) has been found to be associated with increased cell proliferation, metastasis and also act as an indicator of poor prognosis in patients with breast cancer. Therefore, new agents that can abrogate CXCR4 expression have potential against breast cancer metastasis. In this study, we examined the potential effect of thymoquinone (TQ), derived from the seeds of Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. TQ was found to inhibit the expression of CXCR4 in MDA-MB-231 triple negative breast cancer (TNBC) cells in a dose- and time-dependent manner. It was noted that suppression of CXCR4 by TQ was possibly transcriptionally regulated, as treatment with this drug caused down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and suppression of NF-κB binding to the CXCR4 promoter. Pretreatment with a proteasome inhibitor and/or lysosomal stabilization did not affect TQ induced suppression of CXCR4. Down-regulation of CXCR4 was further correlated with the inhibition of CXCL12-mediated migration and invasion of MDA-MB-231 cells. Interestingly, it was observed that the deletion of p65 could reverse the observed anti-invasive/anti-migratory effects of TQ in breast cancer cells. TQ also dose-dependently inhibited MDA-MB-231 tumor growth and tumor vascularity in a chick chorioallantoic membrane assay model. We also observed TQ (2 and 4 mg/kg) treatment significantly suppressed multiple lung, brain, and bone metastases in a dose-dependent manner in a metastasis breast cancer mouse model. Interestingly, H&E and immunohistochemical analysis of bone isolated from TQ treated mice indicated a reduction in number of osteolytic lesions and the expression of metastatic biomarkers. In conclusion, the results indicate that TQ primarily exerts its anti-metastatic effects by down-regulation of NF-κB regulated CXCR4 expression and thus has potential for the treatment of breast cancer.

Johannes Zellner,1 Werner Krutsch,1 Christian G Pfeifer,1 Matthias Koch,1 Michael Nerlich,1 Peter Angele1,2 1Department of Trauma Surgery, University Medical Center Regensburg, Regensburg, Germany; 2Sporthopaedicum, Regensburg, Germany Abstract: Over the last decade, regenerative treatment options have become the more routinely used techniques for treatment of cartilage defects, with predictable outcomes for their specific indications. For large chondral lesions in young patients, in particular, autologous chondrocyte implantation is the treatment of choice for restoration of joint health. This review focuses on indications, results, and outcome predictors of autologous chondrocyte implantation in comparison to other regenerative treatment procedures and discusses improvement options and future perspectives for autologous chondrocyte transplantation. As research activities are increasing in the field of regenerative joint therapy, recent developments may help to overcome remaining limitations step by step. Keywords: ACI, cartilage repair, matrix- associated autologous chondrocyte transplantation, microfracture, osteochondral transplantation

Nutrition and consumer education may be regarded as a constituent part of global education. It is, however, necessary to explore the connections between the specific subject didactics of nutrition and consumer education, and global education more closely within current academic discourse if we are to understand it better. Currently, there is virtually no research or academic writing about these connections in the field of global education and global learning, apart from a few considerations addressing fair trade issues. This article follows an initial, exploratory approach to explore the relationship between nutrition and consumer education, and global education. In this, the role of the state in formal education must be considered insofar as its educational policies on nutrition and consumer education curricula also exert an influence on the syllabus content of nutrition and consumer education. In the new nutrition and consumer education curricula in southern Germany (specifically in Baden-Württemberg in 2016), global aspects of the syllabus are to some extent explicit, as the curriculum analysis will show. Nevertheless, a critical view of the new curricula is necessary to understand how, and how far, it includes global learning concepts. In future, along with an exploratory approach to the relationship between nutrition and consumer education, and global education, as offered by this article, there will also be a need for empirical subject-didactic research to clarify whether and where there are tangencies between nutrition and consumer education, and global learning in everyday teaching praxis. Empirical subject-didactic research in this field has hitherto been lacking, and thus offers a research desideratum.

Since there are no spaces between words to mark word boundaries in Chinese, it is common to see 2 identical neighboring characters in natural text. Usually, this occurs when there are 2 adjacent words containing the same character (we will call such a coincidental sequence of 2 identical characters "repeated characters"). In the present study, we examined how Chinese readers process words when there are repeated characters. In 3 experiments, we compared how Chinese readers process 4-character strings including 2 repeated characters (e.g. [Chinese characters omitted], pinyin: xíngdòng dòngji, meaning "behavioral motivation") with a control condition where none of the characters repeat (e.g. [Chinese characters omitted], pinyin: xíngdòng yùwàng, meaning "behavioral desire"). In Experiment 1, the 4-character strings were presented for 40 ms and participants were asked to report as many characters as possible. Participants reported the second and third characters less accurately in the repeated condition than the control condition. In Experiments 2A and 2B, we embedded 2 different types of 4-character strings, compound Chinese characters and simple Chinese characters, into the same sentence frames, and asked participants to read these sentences normally. Gaze duration and total time on the second word were significantly longer in the repeated condition. These results suggest that the repeated characters increased the difficulty of word processing. Moreover, the results are consistent with the predictions of serial models, which assumes that words are processed serially in reading.

Children and adults use established global knowledge to generate real-time linguistic predictions, but less is known about how listeners generate predictions in circumstances that semantically conflict with long-standing event knowledge. We explore these issues in adults and 5- to 10-year-old children using an eye-tracked sentence comprehension task that tests real-time activation of unexpected events that had been previously encountered in brief stories. Adults generated predictions for these previously unexpected events based on these discourse cues alone, whereas children overall did not override their established global knowledge to generate expectations for semantically conflicting material; however, they do show an increased ability to integrate discourse cues to generate appropriate predictions for sentential endings. These results indicate that the ability to rapidly integrate and deploy semantically conflicting knowledge has a long developmental trajectory, with adult-like patterns not emerging until later in childhood.