tbuckley/cabot-search huggingface dataset:
Abstract 1643: Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group
Authors: Sui Xiong Cai, Qingbing Xu, Lizhen Wu, Feng Yin, Xiuhua Hu, Xiaozhu Wang, Yangzhen Jiang, Qingli Bao, Guoxiang Wang, Xiuyan Zhang, Ye Edward Tian
Journal: Cancer Research (2015)

Abstract Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair and PARP-1 inhibitors have been shown to be effective against cancers with DNA repair defects, such as BRCA1 or BRCA2 mutations. Recently, European Medicines Agency (EMA) recommended approval of PARP-1 inhibitor Olaparib (AZD2281) for the treatment of ovarian cancers with BRCA mutations. In this presentation, we will report our discovery of a series of 1-benzylquinazoline-2,4(1H,3H)-diones (BQD) as novel and potent PARP inhibitors. We will present SAR data for substituents at the 3- and 4-positions of the benzyl group of BQD, and the identification of IMP4297 as a clinical candidate. IMP4297 has advantages in vitro and in vivo over AZD2281. It is not only more potent but also more selective than AZD2281 in cell-based assays, and was 20-fold more efficacious than AZD2281 in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model. IND enabling studies for IMP4297 is in progress with IND submission planned in 12 months. Citation Format: Sui Xiong Cai, Qingbing Xu, Lizhen Wu, Feng Yin, Xiuhua Hu, Xiaozhu Wang, Yangzhen Jiang, Qingli Bao, Guoxiang Wang, Xiuyan Zhang, Ye Edward Tian. Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2015-1643
A universal basic income: the answer to poverty, insecurity, and health inequality?
Authors: Anthony Painter
Journal: BMJ (2016)

Early evidence suggests substantial health dividends

For four years in the mid-1970s an unusual experiment took place in the small Canadian town of Dauphin. Statistically significant benefits for those who took part included fewer physician contacts related to mental health and fewer hospital admissions for “accident and injury.” Mental health diagnoses in Dauphin also fell. Once the experiment ended, these public health benefits evaporated.1 What was the treatment being tested? It was what has become known as a basic income—a regular, unconditional payment made to each and every citizen. This ground breaking experiment, an early randomised trial in the social policy sphere, ran out of money before full statistical analysis after a loss of political interest.

The link between inequality and poor health outcomes is long established.2 The actual mechanisms behind that link are less understood. The data from the Dauphin study, re-examined by a team from the University of Manitoba in the 2000s, suggest …
Abstract 4778: HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells
Authors: Pei-Yin Hsu, Hang-Kai Hsu, Victor X. Jin, Zelton D. Sharp, Tim H.-M. Huang
Journal: Cancer Research (2015)

Abstract Recruitment of transcriptional machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 were frequently amplified (50∼60 copies) and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, the majority of 20q13 DEREs were mobilized to form regulatory depots for synchronized regulation of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and subsequent facilitation of histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dissembled these regulatory depots and reversed this transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of JAK/STAT signaling networks, leading to proliferation inhibition of cancer cells with beneficial outcome of breast cancers. These findings reveal a formerly uncharacterized feature of oncogenic amplicons that multiple copies of the amplicon congregate as transcriptional unions in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies. Citation Format: Pei-Yin Hsu, Hang-Kai Hsu, Victor X. Jin, Zelton D. Sharp, Tim H.-M. Huang. HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2015-4778
574. Sustaining Helper-Dependent Adenoviral Vector-Mediated Human CFTR Expression in Mouse Airways Through Transient Immunosuppression
Authors: Huibi Cao, Jing Wu, Cathleen Duan, Jim Hu
Journal: Molecular Therapy (2015)

Cystic Fibrosis (CF) is a common life-threatening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an epithelial chloride channel. Gene therapy for CF lung disease has been tested extensively. However, sustained expression of the CFTR gene is a major challenge to gene delivery with either viral or no viral vectors. One strategy to improve the persistent CFTR expression is to modulate host immune responses by transient immunosuppression. We showed previously that cyclophosphamide significantly enhanced human CFTR expression in mice received HD-Ad vector readministration, through inhibition of host immune reactions. In this study, we examined cyclophosphamide, dexmethoson, and combination of cyclosporine, methylprednsolone and azathioprine, for their effects on long term expression of the human CFTR delivered with helper-dependent adenoviral (HD-Ad) vectors to mouse airways. Four group mice were nasally delivered with an HD-Ad-K18-CFTR vector at 1.5×10E10 particles per mouse. Three groups were treated with immunesuppresants and one group without any treatment was used as a control. The immunosuppressants were administrated twice, at 6 hours before and 48 hours after nasal delivery of the HD-Ad-CFTR vector. Expression of the CFTR gene was assessed 4 months after vector administration. We found that cyclophosphamide has significantly improved the sustained expression of the CFTR gene (2.5 times higher) compared to the no treatment group as determined by real-time qPCR. It alsogreatly reduced the levels of anti-adenoviral and neutralizing antibodies in both BALF and serum. However, cyclophosphamide did not show major effects on the innate immune reaction to HD-Ad vectors, such as NK cell infiltration and activation, 4 days after vector delivery. Dexmethesone also greatly reduced neutralizing antibodies production, but not affected transgene expression. A combination of cyclosporine, methylprednsolone and azathioprine which is used to suppress immune reactions in lung transplantation, also did not affect CFTR gene expression, nor immune reactions following HD-Ad-CFTR vector delivery. These data demonstrate that transient administration of cyclophosphamide can significantly improve sustained HD-Ad-mediated transgene expression in mice and it is more effective than dexmethsone or the combination of cyclosporine, methylprednsolone and azathioprine.
The Role of Endogenous Stromal Cell-Derived Factor-1 in the Survival and Growth of Acute Myeloid Leukemia Cells
Authors: Ha-Yon Kim, Yoon-Suk Oh, Ik-Chan Song, Hyo-Jin Lee, Hwan-Jung Yun, Samyong Kim, Deog-Yeon Jo
Journal: Blood (2011)
Abstract LB-266: Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol
Authors: Sung Hee Choi, Emily Baker, Byung-Gyu Kim, Gregory Tochtrop, John J. Letterio
Journal: Cancer Research (2015)

Abstract Celastrol is a natural triterpenoid isolated from the medicinal herb Triptyrgium wilfordii, commonly known as the Thunder of God vine. Celastrol has been shown to have a broad range of anti-inflammatory and anti-cancer activities. Here we investigated whether celastrol administered as a dietary supplement can inhibit both colitis and colitis-associated colon cancer (CAC) in either genetic or chemically-induced CAC mouse models. As a genetic and spontaneous, inflammatory-driven intestinal neoplasia model, we generated a Smad4TKO / p27Kip1-/- (DKO) mouse in which a germ line p27Kip1 gene deletion (p27Kip1-/-) was combined with the T cell-restricted deletion of the Smad4 gene (Smad4TKO). All DKO mice developed spontaneous gastrointestinal inflammation and colon carcinoma by 3 months of age. Administration of celastrol as a dietary supplement (2 mg/day) to DKO mice increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators, including TNF-alpha, IL-6, IL-1beta and iNOS. We investigated the chemopreventive activity of celastrol in the chemically induced CAC mouse model using dextran sulfate sodium (DSS)/azoxymethane (AOM). Mice (C57/BL6, ages 6-8 weeks) received intraperitoneal injections with 10 mg/kg AOM, followed by exposure to 2% DSS in drinking water for 7 days. We repeated 3 cycles of 2% DSS, with 10 days of normal drinking water provided between cycles. Mice were either maintained on control diet or given celastrol (2 mg/day) diet beginning with first administration of DSS and continuing until termination of the experiment. Mice receiving celastrol diet showed less loss in body weight compared with the control diet group and marked protection from AOM/DSS-induced colon cancer. The incidence and number of colonic tumors in mice in the celastrol diet group were also significantly lower than those in control diet group. These results were accompanied by decreased expression of iNOS and lower production of pro-inflammatory cytokines. Our data demonstrate the protective effects of celastrol in the chemoprevention of CAC, was and this effect correlated with a dampening of iNOS expression and with a decrease of inflammatory cytokine production. These results highlight the potential of celastrol as an effective agent for the chemoprevention of CAC in humans. Citation Format: Sung Hee Choi, Emily Baker, Byung-Gyu Kim, Gregory Tochtrop, John J. Letterio. Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-266. doi:10.1158/1538-7445.AM2015-LB-266
Abstract 1030: Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity
Authors: Yang-an Wen, Xin Li, Tatiana Goretsky, Terrence A. Barrett, Tianyan Gao
Journal: Cancer Research (2015)

Abstract Background &amp; Aims: PHLPP, a novel family of protein phosphatases, plays an important role in balancing cellular signaling pathways that control cell death and proliferation. Loss of PHLPP expression promotes colorectal cancer (CRC) tumorigenesis and progression. Intestine epithelial cells (IECs) apoptosis contributes to the development of inflammatory bowel disease (IBD), and patients with IBD are at increased risk for CRC. We investigated the functional importance of PHLPP in intestinal inflammation. Methods: Both Phlpp1 and Phlpp2 genes were deleted in mice. The effect of PHLPP double knockout (DKO) on the development of acute colitis was examined in dextran sulfate sodium salt (DSS)-treated mice. Biochemical and histological analyses were conducted to determine the extent of tissue inflammation and colon epithelial cell apoptosis. The expression of PHLPP proteins was examined in DSS-treated mice and IBD patient samples. Results: In ulcerative colitis and Crohn's disease patient samples, both PHLPP1 and PHLPP2 protein expression was markedly decreased in colitis tissues compared to that in uninvolved tissues. In mice, PHLPP expression was significantly reduced in colonic epithelial cells following induction of colitis by DSS. Mechanistically, the inflammation-induced downregulation of PHLPP was mediated through proteasome-dependent protein degradation. Compared with wild-type mice, PHLPP DKO mice were protected from colitis induced by the DSS treatment as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in colonic epithelial cells. Furthermore, epithelial organoids derived from colon and small intestine of PHLPP DKO mice are more resistant to inflammation-induced apoptosis upon Akt activation. Conclusion: These results indicated that PHLPP contributes to the pathogenesis of colitis by controlling epithelial cell apoptosis. Downregulation of PHLPP at the onset of inflammation plays a role in protecting intestinal epithelial cell injury by inhibiting apoptosis. However, prolonged PHLPP-loss may promote colon cancer initiation in IBD patients. Citation Format: Yang-an Wen, Xin Li, Tatiana Goretsky, Terrence A. Barrett, Tianyan Gao. Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1030. doi:10.1158/1538-7445.AM2015-1030
Mutational Profiling of Multiple Myeloma Bone Marrow Aspirates As a Clinical Tool for Personalized Treatment of Myeloma
Authors: Anuj Mahindra, Dora Dias-Santagata, Darrell Borger, Loredana Santo, Tyler A. Scullen, Andrew Yee, Homare Eda, Diana Cirstea, Anthony John Iafrate, Noopur Raje
Journal: Blood (2012)
miR-10b-5p is a novel Th17 regulator present in Th17 cells from ankylosing spondylitis
Authors: L Chen, M H Al-Mossawi, A Ridley, T Sekine, A Hammitzsch, J de Wit, D Simone, H Shi, F Penkava, M Kurowska-Stolarska, I Pulyakhina, J C Knight, TJ Kim, P Bowness
Journal: Annals of the Rheumatic Diseases (2016)

To determine the microRNA (miR) signature in ankylosing spondylitis (AS) T helper (Th)17 cells. Interleukin (IL)-17A-producing CD4+ T cells from patients with AS and healthy controls were FACS-sorted for miR sequencing and qPCR validation. miR-10b function was determined by miR mimic expression followed by cytokine measurement, transcriptome analysis, qPCR and luciferase assays. AS Th17 cells exhibited a miR signature characterised by upregulation of miR-155-5p, miR-210-3p and miR-10b. miR-10b has not been described previously in Th17 cells and was selected for further characterisation. miR-10b is transiently induced in in vitro differentiated Th17 cells. Transcriptome, qPCR and luciferase assays suggest that MAP3K7 is targeted by miR-10b. Both miR-10b overexpression and MAP3K7 silencing inhibited production of IL-17A by both total CD4 and differentiating Th17 cells. AS Th17 cells have a specific miR signature and upregulate miR-10b in vitro. Our data suggest that miR-10b is upregulated by proinflammatory cytokines and may act as a feedback loop to suppress IL-17A by targeting MAP3K7. miR-10b is a potential therapeutic candidate to suppress pathogenic Th17 cell function in patients with AS.
PTH-083 is there a relationship between gluten free diet adherence and symptomatic responses to gluten in coeliac disease?
Authors: S M Barratt, J S Leeds, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> The gluten-free diet (GFD) is the mainstay of treatment in Coeliac Disease (CD). Many individuals report difficulty adhering to the diet facing social obstacles in which inadvertent exposure to gluten occurs. There are limited data surrounding the character, timing and severity of symptomatic responses to dietary gluten. We wished to assess if there was a relationship between adherence and the development of symptoms when exposed to gluten. <h3>Methods</h3> Postal survey (n=224) of CD patients with histologically proven disease. Questionnaire included an assessment of GFD adherence level normally achieved with psychological wellbeing assessed by The Hospital Anxiety and Depression Scale (HADS). Method of presentation (MOP) and disease duration were ascertained by medical records. Patients were categorised into typical- gastrointestinal (GI) symptoms (n=138), atypical- no GI symptoms (n=41) and screening (n=36). <h3>Results</h3> Individuals reporting GFD adherence “All the time” (n=159) were less likely to experience bloating (OR 0.54) and fatigue (OR 0.5) compared to individuals with “Partial/None” adherence in response to dietary gluten (p=&lt;0.05). Crucially, the consistently adherent group were more likely to experience symptoms quicker (&lt;1 h) and to a greater severity than partial/none adherent respondents since starting the GFD (OR 1.8 and OR 2.3, respectively, p=0.01). Individuals with screening MOP reported less abdominal pain, diarrhoea and bloating in response to gluten compared to typical and atypical. However, atypical MOP was associated with an increase in headaches (p=&lt;0.05). In response to gluten individuals with HADS scores suggesting anxiety and depression were more likely to experience abdominal pain, headaches, insomnia, mouth ulcers, fatigue and nausea compared to those with low HADS scores (p=&lt;0.05). Anxiety alone was associated with more abdominal pain and insomnia in response to gluten (p=&lt;0.05). Disease duration had no impact on symptomatic responses. <h3>Conclusion</h3> We are the first group to describe that there is a relationship between GFD adherence and the development of symptoms on exposure to gluten. This may be because of the initial MOP (which ensures subsequent GI symptoms if exposed to gluten) or because adherent patients are more likely to have “immune tolerance” and thus develop more severe symptoms when exposed to gluten. It is also interesting to note that the presence of anxiety and depression means more symptoms (when exposed to gluten) or are these individuals just more sensitive to their symptoms? Further prospective longitudinal data are required to support our preliminary observations. Our data may suggest that certain groups of patients could be identified where follow-up is essential in order to ensure optimal adherence.
Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis
Authors: Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Rikuka Shimizu, Yutaka Takazawa, Takuro Nakamura
Journal: Cancer Research (2016)

Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer Res; 77(4); 897-907. ©2016 AACR.
Abstract #2325: Inhibitor of Src kinase SKI-606 (Bosutinb) blocks prostate cancer growth, invasion and experimental skeletal metastases in vitro and in vivo by regulating the expression of key intracellular signaling molecules and genes involved in prostate cancer progression
Authors: Shafaat Rabbani, Maria-Luisa Valentino, Suhad Ali, Frank Boschelli
Journal: Cancer Research (2009)

Members of the  Src  family of non receptor tyrosine kinases play a critical role in cell proliferation, migration and invasion. Combined with the ability to regulate the expression of key genes involved in tumor progression, the  Src  oncogene plays a central role in the development and progression of several malignancies including prostate cancer. In the current study, we have examined the efficacy of a  Src/Abl  kinase inhibitor (SKI-606) for its effect on prostate cancer cells migration, invasion, growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 with different doses of SKI-606 decreased tumor cell proliferation, migration and invasion as determined by Matrigel Boyden chamber invasion assay. For  in vivo  studies PC-3 cells were inoculated via subcutaneous (s.c) or intra tibial (i.t) route into male Balb c nu/nu or Fox Chase SCID mice respectively. Animals were randomized and treated with vehicle alone or SKI-606 (150 mg/kg) via oral gavage. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume as compared to control animals. In other studies, treatment with SKI-606 resulted in a significant decrease (50%) in experimental skeletal lesion area as evaluated by X-ray using Faxitron and a marked increase (32%) in bone volume to tumor volume ratio (BV/TV) as determined by µCT analysis of tibias from control and experimental groups of animals. Western blot analysis of PC-3 cells treated with SKI-606 showed a significant decrease in phosphorylation of key signaling molecules like AKT, MAPK and FAK. In addition, SKI-606 treatment decreased expression of tumor progression associated genes uPAR, MMP-2, MMP-9, Fibronectin and N-Cadherin and increased the expression of E-cadherin and TIMP-2. Collectively results from these studies provide convincing evidence for the role of  Src  inhibitors to modulate intracellular signaling pathways and expression of genes involved in tumor invasion and metastasis. The ability of  Src  inhibitor SKI-606 currently in clinical trials for various cancers to exhibit these effects in prostate cancer provides compelling evidence to evaluate its efficacy in prostate cancer patients.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2325.
Gastric gastrointestinal stromal tumor presenting with an intraluminal draining abscess and left pleural effusion
Authors: Mariana Cardoso, Luís Lourenço, Ana Oliveira, José Boléo-Tomé, Jorge Reis
Journal: Endoscopy (2016)

A previously healthy 77-year-old woman presented with a 2-month history of anorexia, fever, and weight loss. On physical examination, she had diminished breath sounds in the lower two-thirds of the left hemithorax; her chest radiograph revealed a left pleural effusion ([Fig. 1]). Laboratory work-up showed a hemoglobin of 9.6 g/dL, C-reactive protein (CRP) of 9.5 mg/dL, and erythrocyte sedimentation rate (ESR) of 70 mm/hour. Because of a family history of pulmonary tuberculosis, a tuberculous pleural effusion was suspected.