tbuckley/cabot-search huggingface dataset:
Abstract 5182: Targeting abnormal metabolism downstream of MYC in atypical teratoid/rhabdoid tumors
Authors: Sabrina Wang, Jeffrey Rubens, Sariah Allen, Brent Orr, Charles Eberhart, Eric Raabe
Journal: Cancer Research (2017)

Abstract Atypical teratoid rhabdoid tumors (AT/RT) are deadly infantile brain tumors in dire need of new, targeted therapies. Recent molecular analysis revealed considerable tumor heterogeneity subdividing AT/RT into 3 distinct groups. The MYC subgroup has a dismal 5 year survival of 18.5%. MYC is known to drive reliance on glutamine for cellular metabolism suggesting that high-MYC expressing neoplasms may be sensitive to glutamine metabolic inhibitors. 6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist that decreases the tumorigenicity of high MYC expressing models of medulloblastoma and neuroblastoma . We hypothesize that DON will reduce the tumorigenicity of the MYC subgroup of AT/RT. High levels of c-MYC protein are expressed in about 1/3 of human AT/RT (Immunohistochemistry for c-MYC on 22 human AT/RT, H-score &amp;gt; 1 standard deviation over the median considered high c-MYC expression). Similarly two of six of AT/RT cell lines expressed high levels of c-MYC protein by western blot. DON treatment slowed cell growth of high c-MYC expressing AT/RT cell lines BT12 and CHLA06 (MTS assay p&amp;lt;0.005 10uM DON vs DMSO control; t-test), whereas cell lines BT37 and CHLA05, which had low c-MYC expression were not affected. Cell cycle analysis demonstrated that DON caused cell cycle arrest in the G2/M phase for the high c-MYC expressing lines BT12 and CHLA06 (31.2% of BT12 DMSO controls in G2/M phase vs 54.5% after 10uM DON treatment and 27.4% vs 48.9% in CHLA06). In contrast the cell cycle was not affected by DON treatment in the cell lines with low c-MYC expression (21.3% DMSO vs 20.2% after 10uM DON in BT37). DON also increased apoptosis in cell lines with high c-MYC and induced DNA strand breaks (Western blot for c-PARP and p-H2A.X respectively). DON significantly improved survival in BT-12 high c-MYC expressing orthotopic mouse xenografts (median survival increased from 21 to 36 days, p&amp;lt;0.005; log-rank test). These data develop the framework for future clinical trials using glutamine antagonists to target the MYC subgroup of AT/RT. Citation Format: Sabrina Wang, Jeffrey Rubens, Sariah Allen, Brent Orr, Charles Eberhart, Eric Raabe. Targeting abnormal metabolism downstream of MYC in atypical teratoid/rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5182. doi:10.1158/1538-7445.AM2017-5182
Abstract 41: An Antibody Drug Conjugate targeting HER-3 demonstrates promising antitumor efficacy in a wide range of human cancer
Authors: Gianluca Sala, Manuela Iezzi, Alessia Lamolinara, Emily Capone, Stefano Iacobelli, Jean-Fred Sauniere, Sara Ponziani, Francesco Giansanti, Rodolfo Ippoliti
Journal: Cancer Research (2017)

Abstract The HER-3 receptor is emerging as an attractive molecule in therapeutics because of its overexpression across many human cancers and because of its role in in several compensatory processes that underlay emergence of resistance to certain cancer drugs. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ADC) targeting HER-3. It consists of a humanized HER-3 monoclonal antibody (mAb EV20), which recognizes the HER-3 extracellular domain, conjugated to different payloads (HER-3-ADC)s. In HER-3 expressing cancer cell lines, these HER-3-ADCs demonstrated a powerful, specific and target-dependent killing activity. High expression levels of HER-3 in tumor cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Efficacy studies demonstrated that HER-3-ADCs treatment leads to a long lasting tumor growth inhibition of cell line-based models of human head and neck, breast, pancreatic, prostatic, lung, stomach cancers and melanoma. Overall, these findings validate HER-3 as an attractive therapeutic target in multiple solid tumors and support further clinical development and application of HER-3 targeting ADCs. Citation Format: Gianluca Sala, Manuela Iezzi, Alessia Lamolinara, Emily Capone, Stefano Iacobelli, Jean-Fred Sauniere, Sara Ponziani, Francesco Giansanti, Rodolfo Ippoliti. An Antibody Drug Conjugate targeting HER-3 demonstrates promising antitumor efficacy in a wide range of human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2017-41
Abstract 2493: Identification of the mutant p53-PARP-MCM chromatin axis as a triple negative breast cancer replication stress target
Authors: Wei-Gang Qiu, Alla Polotskaia, Gu Xiao, Lia Di, Yuhan Zhao, Wenwei Hu, John Philip, Ronald Hendrickson, Jill Bargonetti
Journal: Cancer Research (2017)

Abstract Approximately 15% of all breast cancer is triple-negative and of these about 80% are found to have mutations in the gene for the tumor suppressor p53 (TP53). Many TP53 mutations encode gain-of-function oncogenic mutant p53 (GOF mtp53) protein. We used inducible knockdown of endogenous GOF mtp53 in MDA-MB-468 cells in conjunction with stable isotope labeling with amino acids in cell culture (SILAC) and subcellular fractionation. We sequenced over 70,000 total peptides for chromatin and cytoplasmic reciprocal data sets and were able to identify 3,010 unique cytoplasmic fraction proteins and 3,403 unique chromatin fraction proteins. We found that the heterohexomeric minichromosome maintenance (MCM) complex (MCM 2-7) along with PARP are high mtp53-chromatin associated pathways. When we depleted R273H mtp53 we found a large reduction of the amount of MCM complex and PARP proteins on the chromatin. Furthermore a direct mtp53-MCM2 interaction was detected. Overexpressed mtp53, but not wild type p53, showed a protein-protein interaction with MCM2 and MCM4. We treated cells with the PARP inhibitor talazoparib and the alkylating agent temozolomide and detected synergistic activation of apoptosis only in the presence of functional MCM2-7 and mtp53. The mtp53-PARP-MCM axis has potential use as a therapeutic and diagnostic target. Citation Format: Wei-Gang Qiu, Alla Polotskaia, Gu Xiao, Lia Di, Yuhan Zhao, Wenwei Hu, John Philip, Ronald Hendrickson, Jill Bargonetti. Identification of the mutant p53-PARP-MCM chromatin axis as a triple negative breast cancer replication stress target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2493. doi:10.1158/1538-7445.AM2017-2493
Abstract 5376: Requirement of TET2 in MLL-AF9 mediated leukemogenesis
Authors: Dipmoy Nath, Golam Mohi
Journal: Cancer Research (2017)

Abstract TET methylcytosine dioxygenase 2 (TET2) catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine resulting in DNA demethylation. Loss-of-function mutations or deletions of TET2 have been found in several myeloid malignancies including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). Moreover, deletion of TET2 leads to myeloid malignancies in mice. Therefore, TET2 has been suggested to play a tumor suppressor role in myeloid malignancies. In this study, unexpectedly, we have uncovered a tumor promoter function for TET2 in MLL rearranged leukemia. Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene have been found in ~10% of acute leukemia and are associated with poor prognosis. We observed that depletion of TET2 significantly inhibited the proliferation of MLL-AF9 positive MOLM14 leukemia cells. Similarly, knockdown of TET2 markedly reduced proliferation in murine Ba/F3 cells stably expressing MLL-AF9. Conversely, overexpression of TET2 significantly increased proliferation in MLL-AF9 expressing MOLM14 and Ba/F3 cells. In addition, deletion of TET2 significantly inhibited MLL-AF9 mediated myeloid colony formation in the bone marrow (BM) cells ex vivo. Next, we assessed the in vivo effects of TET2 deletion in MLL-AF9-mediated leukemogenesis using retroviral bone marrow transduction and transplantation assays. Whereas recipients of MLL-AF9-transduced wild type BM exhibited marked increase in white blood cells (WBC) and neutrophils in their peripheral blood and significant increase in the spleen size, recipients of MLL-AF9-transduced TET2-deficient BM showed significantly reduced WBC and neutrophil counts and reduced spleen size. Flow cytometric analysis showed significantly increased myeloid precursors (Gr-1+/Mac1+) and granulocyte macrophage progenitors (GMP) in the BM of transplanted animals receiving MLL-AF9 expressing wild type BM compared with recipients of MLL-AF9 expressing TET2-deficient BM. Furthermore, transplanted animals receiving MLL-AF9-transduced wild type BM showed marked increase in hematopoietic stem/progenitor cells (LSK; Lin-Sca-1+c-kit+), which was significantly reduced upon TET2 deletion. Deficiency of TET2 also significantly reduced MLL-AF9-mediated increase in hematopoietic progenitor colony formation in the BM. In addition, deletion of TET2 resulted in increased overall survival in mice expressing MLL-AF9. Together, these data indicate that TET2 is required for leukemic transformation mediated by MLL-AF9. Our results suggest a novel tumor promoter function for TET2 in MLL rearranged leukemia. Citation Format: Dipmoy Nath, Golam Mohi. Requirement of TET2 in MLL-AF9 mediated leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5376. doi:10.1158/1538-7445.AM2017-5376
Abstract 2387: Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer
Authors: Jie Yi, Yu Chen, Ran Gao, Zhuo Yang, Jinhua Wang, Yingchun Xu
Journal: Cancer Research (2017)

Abstract NSUN2 is a RNA methyltransferase that has been shown to be implicated in development of human cancer. However, the functional role of NSUN2, mechanism of NSUN2 overexpression and its association with clinicopathologic features in breast cancer remain unclear. To investigate alterations in the expression and functional role of NSUN2 in breast cancer, NSUN2 expression was assessed in breast cancer cells and tissues obtained from cancers at different American Joint Committee on Cancer (AJCC) stages, and its functions were investigated using breast cancer cells. NSUN2 expression was shown to be significantly higher in breast cancer cells and tissues than in normal breast epithelial cells and tissues, at both mRNA and protein levels. Overexpression of NSUN2 was shown to promote cell proliferation, migration, and invasion while NSUN2 knockdown inhibited these processes in vitro and in vivo. NSUN2 expression level was associated with the methylation level of its promoter. Our results demonstrated that the overall expression of NSUN2 significantly correlated with clinical stage (P=0.027), tumor classification (P=0.012), pathological differentiation (P=0.023), as well as with the expression levels of estrogen receptor (P&amp;lt;0.001), progesterone receptor (P=0.001), and Ki-67 (P&amp;lt;0.001). Our findings provide a unique insight into the roles and effects of NSUN2 overexpression in breast cancer cells, and highlight the necessity of the investigation of novel therapeutic targets, such as NSUN2, for the improvement of breast cancer treatments. Citation Format: Jie Yi, Yu Chen, Ran Gao, Zhuo Yang, Jinhua Wang, Yingchun Xu. Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2017-2387
Abstract 1831: PET/CT imaging of interleukin-13 receptor alpha-2-targeted peptide to glioblastoma after locoregional delivery
Authors: Anirudh Sattiraju, Ang Xuan, Frankis Almaguel, Denise Herpai, Waldemar Debinski, Akiva Mintz, Kiran Kumar Solingapuram Sai
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most aggressive and common primary malignant astrocytoma which is characterized by tumor heterogeneity, infiltrating margins. Radiotherapy, chemotherapy and experimental targeted therapies have been ineffective at meaningfully increasing patient survival. One significant shortcoming of systemically delivered therapies is their inability to cross the blood brain barrier (BBB) and access infiltrating tumor cells. Therefore, in this work, we tested the potential of locoregionally targeting GBM via IL13Rα2, which we discovered to be expressed on greater than 75% of GBMs. To accomplish this, we intracranially infused copper-64 (64Cu) radiolabeled IL13Rα2 specific peptide Pep-1L, previously developed by Pandya et al., into mice bearing IL13Rα2 expressing orthotopic GBMs. Small animal micro PET/CT imaging showed ~2-fold greater tumor specific localization and lower volume of distribution of 64Cu-Pep-1L within brains of mice. Post-PET biodistribution study showed greater retention of 64Cu-Pep-1L 4 hours (%ID/g = 20.85± 0.65) and 24 hours (%ID/g = 14.65± 0.30) post infusion when compared to similarly infused 64Cu radiolabeled scrambled control peptide 4 hours (%ID/g = 10.73± 2.02) and 24 hours (%ID/g = 5.97± 1.47) post infusion. These results demonstrate that Pep-1L efficiently targets IL13Rα2 expressing GBMs in vivo upon loco-regional delivery and can effectively deliver potential therapeutic agents to GBM tumors while sparing normal brain. This work was supported by the American Cancer Society Mentored Research Scholar grant # 124443-MRSG-13-121-01-CDD (Mintz), 1R01CA179072-01A1 (Mintz), P30 CA012197 (Pasche), R01CA07414519 (Debinski) and the Translational Imaging Program (TIP) of the Wake Forest CTSA (UL1TR001420). Citation Format: Anirudh Sattiraju, Ang Xuan, Frankis Almaguel, Denise Herpai, Waldemar Debinski, Akiva Mintz, Kiran Kumar Solingapuram Sai. PET/CT imaging of interleukin-13 receptor alpha-2-targeted peptide to glioblastoma after locoregional delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1831. doi:10.1158/1538-7445.AM2017-1831
Charlie Gard dies in hospice after High Court rules against prolonging life support
Authors: Susan Mayor
Journal: BMJ (2017)

Charlie Gard, the terminally ill baby with infantile onset encephalomyopathic mitochondrial DNA depletion syndrome, died on Friday 28 July. He was taken off a ventilator after a High Court ruling that life support should not be prolonged.

After abandoning their four month legal battle with Great Ormond Street Hospital for Children for Charlie to be flown to the US for experimental treatment, his parents, Connie Yates and Chris Gard, applied to the High Court on Monday 24 July asking that they could spend “a week or so” in a hospice with their son before he was taken off the ventilator.

The High Court judge Mr Justice Francis ruled that they had until 12 noon on 27 July to …
NICE guidelines could put 12 million UK adults on statins
Authors: Nigel Hawkes
Journal: BMJ (2017)

Almost all men over 60 and all women over 75 in England qualify for statin prescriptions under guidelines adopted by the National Institute for Health and Care Excellence (NICE) in 2014, a new analysis shows.1

Some 11.8 million people in England—37% of adults aged 30 to 84—exceed the threshold set by NICE for prescribing statins, the authors found. They said that most of these patients (9.8 million) are healthy, with no history of cardiovascular events, and are eligible for treatment simply because they exceed the risk threshold set by NICE: a 10% risk of experiencing such an event in the next 10 years.

Even some people with no risk factors at all are part of this group by virtue of their age. Nearly all men exceed the 10% threshold by age 65, and all women do so by age 70, even if they are non-smokers of normal weight with …
Management of infantile colic
Journal: BMJ (2013)

Although infantile colic is considered to be a self limiting and benign condition, it is often a frustrating problem for parents and caregivers. It is a frequent source of consultation with healthcare professionals and is associated with high levels of parental stress and anxiety.1 2

Several published reviews of the literature have explored dietary, pharmacological, complementary, and behavioural therapies as options for the management of infantile colic.1 3 Here, we assess whether these management options are supported by the literature and if there are any novel treatment options.

Infantile colic has been defined as paroxysmal uncontrollable crying in an otherwise healthy infant less than 3 months of age, with more than three hours of crying per day in more than three days a week and for more than three weeks.4 5 It is known to have a significant impact on infants and their families, with up to one in six families with children with symptoms of colic consulting healthcare professionals.6

Despite the prevalence of the condition, the pathogenesis remains incompletely understood. One hypothesis has suggested that infantile colic is caused by the impact of abnormal gastrointestinal motility and pain signals from sensitised pathways in the gut viscera.2 Another hypothesis is that inadequate amounts of lactobacilli and increased amounts of coliform bacteria in the intestinal microbiota influences gut motor function and gas production, which subsequently contributes to the condition.2

More controversially, behavioural issues such as family tension, parental anxiety, or inadequate parent-infant interaction have also been explored as causative factors for infantile colic.1 In addition, little is known about concomitant risk factors; however, maternal smoking, increased maternal age, and firstborn status are thought to be associated with the development of infantile colic. No association with feeding method has been noted.1

As a consequence …
Abstract 3536: The role of Nuclear factor I transcription factors in glioma
Authors: Kok Siong Chen, Linda J. Richards, Jens Bunt
Journal: Cancer Research (2017)

Abstract Gliomas are the most common brain tumors in adults. Among the malignant gliomas, grade IV glioma, or glioblastoma (GBM), is the most aggressive form. Despite harsh treatments such as surgery, radiotherapy and chemotherapy, the median survival of GBM patients remains at just 12-15 months. GBM tumors could originate from cells of the glial lineage that have escaped the normal glial differentiation mechanisms. Therefore, by applying knowledge about normal glial development, we might understand how pathways that normally drive differentiation are affected in these tumors. If reactivating these pathways induces the differentiation of proliferative tumor cells, we could use this as a novel target for therapy. Our research is focused on the Nuclear factor I (NFI) transcription factors, one of the key factors to induce glial differentiation during normal development and is implicated in glioma. In insertional mutagenesis glioma mouse models, Nfi genes are consistently disrupted, suggesting a role for NFI in glioma initiation. Furthermore, loss of NFIB is common in human astrocytoma, while loss of NFIA is associated with oligodendroglioma. To determine whether loss of Nfi alters glioma initiation, progression or tumor histology, we have crossed inducible glioma mice with conditional Nfi deletion mice to follow tumor initiation and progression using fluorescence imaging and immunohistochemistry. Based on analyses of glioma mRNA expression data sets, NFIB expression correlates inversely with tumor grade and survival. Using immunofluorescence, we determined that both NFIA and NFIB are mainly expressed within the non-proliferative cells in GBM tissue, suggesting that NFI may play a direct role in tumor cell differentiation. To establish whether NFI expression can indeed inhibit tumor proliferation and induce differentiation, U251 GBM cells were transfected with NFI. While overexpression of NFIA and NFIB reduced cell proliferation, an NFI dominant-negative protein enhanced proliferation. We are currently validating these finding in vivo by electroporating NFI expression constructs into patient-derived GBM xenografts in mice. Our preliminary data show NFIB electroporated cells are indeed differentiated and non-proliferative. Our data suggests that NFI-mediated glial differentiation can be induced in glioma to inhibit tumor growth and may prevent recurrence. Hence, activation of NFI could be a potential target for a glial differentiation-based approach to treat glioma. Citation Format: Kok Siong Chen, Linda J. Richards, Jens Bunt. The role of Nuclear factor I transcription factors in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2017-3536
Revisiting the Page &amp; Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later
Authors: George Hajishengallis, Jonathan M. Korostoff
Journal: Periodontology 2000 (2017)

In their classic 1976 paper, Page & Schroeder described the histopathologic events and the types of myeloid cells and lymphocytes involved in the initiation and progression of inflammatory periodontal disease. The staging of periodontal disease pathogenesis as 'initial', 'early', 'established' and 'advanced' lesions productively guided subsequent research in the field and remains fundamentally valid. However, major advances regarding the cellular and molecular mechanisms underlying the induction, regulation and effector functions of immune and inflammatory responses necessitate a reassessment of their work and its integration with emerging new concepts. We now know that each type of leukocyte is actually represented by functionally distinct subsets with different, or even conflicting, roles in immunity and inflammation. Unexpectedly, neutrophils, traditionally regarded as merely antimicrobial effectors in acute conditions and protagonists of the 'initial' lesion, are currently appreciated for their functional versatility and critical roles in chronic inflammation. Moreover, an entirely new field of study, osteoimmunology, has emerged and sheds light on the impact of immunoinflammatory events on the skeletal system. These developments and the molecular dissection of crosstalk interactions between innate and adaptive leukocytes, as well as between the immune system and local homeostatic mechanisms, offer a more nuanced understanding of the host response in periodontitis, with profound implications for treatment. At the same time, deeper insights have generated new questions, many of which remain unanswered. In this review, 40 years after Page & Schroeder proposed their model, we summarize enduring and emerging advances in periodontal disease pathogenesis.