Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.Cell Death and Differentiation advance online publication, 22 April 2016; doi:10.1038/cdd.2016.37.

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The measurement of circulating cell-free DNA (cfDNA) may transform the management of breast cancer patients. We aimed to investigate the clinical significance of sequential measurements of ESR1 mutations in primary breast cancer (PBC) and metastatic breast cancer (MBC) patients.
ESR1 mutations ratio in the PBC groups was used as the minimum cutoff for determining increases in cfDNA ESR1 mutation ratio. An increase in cfDNA ESR1 mutations was found in 13 samples of cfDNA from 12 (28.6%) out of 42 MBC patients. A total of 10 (83.3%) out of 12 MBC patients with increase cfDNA ESR1 mutations showed a poor response to treatment. In survival analysis, increase cfDNA  mutations may predict a shorter duration of post-endocrine-therapy effectiveness (P = 0.0033).
A total of 119 patients (253 plasma samples) with breast carcinoma were enrolled in this study. Cases were selected if archival plasma samples were available from PBC before and after treatment and from MBC gathered more than twice at the time of progression. cfDNA was isolated from the 77 PBC patients (154 plasma samples) and from the 42 MBC patients (99 plasma samples). To investigate any changes in each cfDNA ESR1 mutation before and after treatment, we analyzed the difference with cfDNA ESR1 mutations ratio in the first blood sample using droplet digital polymerase chain reaction (ddPCR).
We demonstrate that ddPCR monitoring of the recurrent ESR1 mutation in cfDNA of MBC patients is a feasible and useful method of providing relevant predictive information.

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Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.

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On April 22, 2016 Alligator Bioscience AB is a privately held Swedish biotech company developing immuno-oncology antibodies for directed immunotherapy of cancer (Press release, Alligator Bioscience, APR 22, 2016, View Source [SID1234538693]). Alligator reported that it granted Johnson & Johnson an exclusive, worldwide license to Alligator’s clinical candidate ADC-1013 in an agreement entered in August 2015.

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According to this agreement, Janssen will be responsible for developing ADC-1013 and will assume responsibility for the clinical studies once the ongoing, by Alligator sponsored Phase I dose escalation study is completed. Janssen will have exclusive rights to develop and commercialize ADC-1013 initially targeting a number of solid tumors and hematological cancers and will assume responsibility for all additional research, development, manufacturing, regulatory and commercialization activities.
There has been an amendment of the protocol to expand the current Phase I Clinical Study to include a systemic administration arm. This entitles Alligator to a milestone payment of USD 5M.
Separately Janssen and Alligator have also entered a research collaboration to broaden the pre-clinical data package of ADC-1013. Janssen will reimburse Alligator for 2.5 FTEs and running expenses under this agreement.
"It is very encouraging for the ADC-1013 project and the ongoing Phase I studies that the trials are progressing extremely well and are being expanded by a systemic administration arm. This will give us and our partner Janssen important information for the future development of ADC-1013" said Per Norlén CEO at Alligator Bioscience.

For further information, please contact:
Per Norlén, CEO Alligator Bioscience AB, Office number: +46 46 2864280

About ADC-1013
ADC-1013 is an agonistic fully human monoclonal antibody targeting CD40, an immuno-stimulatory receptor found on antigen-presenting cells such as dendritic cells. Stimulation of CD40 on dendritic cells initiates a process leading to a dramatic increase in T effector cells attacking the tumor. In addition, a tumor-specific memory is established, leading to long-term immunity to the cancer.

This press release contains forward-looking statements, consisting of subjective assumptions and forecasts for the future, and estimates are inherently subject to risks and uncertainties.

(Filing, 10-K, Protalix, 2015, APR 22, 2016, View Source [SID:1234511363])

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