tbuckley/cabot-search huggingface dataset:
Abstract 2930: Niche microenvironments essential for tumor heterogeneity of primary cancer cells
Authors: Shiki Fujino, Norikatsu Miyoshi, Masayuki Ohue, Yusuke Takayashi, Masayoshi Yasui, Hidekazu Takahashi, Naoyuki Haraguchi, Jhunichi Nishimura, Taishi Hata, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori
Journal: Cancer Research (2017)

Abstract Primary culture of cancer cells derived from each patient’s tumor can provide important information of the “individual tumor.” It is general to use cell lines in basic research filed. However, cell lines are quite different from clinical cancers. Clinical cancer tissues are composed of not only cancer cells but also tumor microenvironments such as stromal cells and tumor vessels. The primary culture method of clinical cancer with tumor niche microenvironments has not been optimized. We have developed a simple 2D-culture method for primary colorectal cancer (CRC). We obtained 30 samples from surgically resected tumor. They were mechanically and enzymatically digested and fibrotic tissue and bacteria were excluded using customized two size filters. And we cultured the obtained cells on a matrigel-coated plate with embryonic stem (ES) cells culture medium. We named these cultured cancer cells, “isolated-tumor derived Cancer Cells (iCCs).” All iCCs grew and about 80 % of iCCs were successfully passaged. Twenty-three iCCs were transplanted into the subcutaneous layer of NOD-SCID mice, and the tumor growth and histology of iCCs were examined. The morphology was similar to each parental clinical tumor. And microarray analysis showed that RNA expression of iCCs was similar to each parental tumor. Furthermore, we examined the culture medium; our modified ES culture medium (ES-cultured iCCs) and 10% FBS medium (serum-cultured iCCs). The expression of surface markers regarding cancer stem cells such as CD44 and CD24 were different between ES-cultured iCCs and serum-cultured iCCs, and drug sensitivity of iCCs were also different. FACS analysis and immunocytochemistry revealed that iCCs contained PDGFR-positive cells. The results of multi-drug sensitivity assay were different between iCCs and cell lines especially in PDGFR inhibitor. Strong correlations were observed between the results of multi-drug sensitivity assay of iCCs and clinical outcomes of chemotherapy. We report an innovative primary culture method and the in vivo and in vitro analyses of iCCs, leading to the future application. Citation Format: Shiki Fujino, Norikatsu Miyoshi, Masayuki Ohue, Yusuke Takayashi, Masayoshi Yasui, Hidekazu Takahashi, Naoyuki Haraguchi, Jhunichi Nishimura, Taishi Hata, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori. Niche microenvironments essential for tumor heterogeneity of primary cancer cells [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 2930. doi:10.1158/1538-7445.AM2017-2930
Targeting Oxphos Pathway Against Ibrutinib Resistance to Mantle Cell Lymphoma
Authors: Yang Liu, Taylor Bell, Hui Zhang, Yuting Sun, Carrie J Li, Ningping Feng, Shengjian Huang, Hui Guo, Jack Wang, Makhdum Ahmed, Victoria Zhang, Laura T Lam, Krystle Nomie, Liang Zhang, Maria E Di Francesco, Joe Marszalek, Michael Wang
Journal: Blood (2016)
Synthesis of substituted 1,3,4-oxadiazolyl tetrahydropyridines as anticancer agents
Authors: Kinfe Redda, Madhavi Gangapuram
Journal: Cancer Research (2007)

3981  The chemistry of substituted 1,3,4-oxadiazoles and their derivatives received considerable attention during the last decade as potential antimicrobial, antifungal, anti-inflammatory, analgesic, CNS-stimulating, anticonvulsive, anti-cancer, diuretic and antihypertensive agents. Functionalized tetrahydropyridine (THP) ring systems are widely found in biologically active natural products and pharmaceuticals. The anti-inflammatory and anticancer activities of compounds consisting of a reduced pyridine system have been investigated. From our previous research, it was evident that the pharmacological activities of the tetrahydropyridine (THP) derivatives depended on the nature of the substituents on the THP ring system. Incorporation of potential THP moiety may enhance biological activity of 1,3,4-oxadiazole derivatives. Hence, it was planned to synthesize 1,3,4-oxadiazolyl tetrahydropyridines and study their anti-cancer activities. Here, we report the synthesis and anti-cancer activity profiles of a novel series of 1,3,4-oxadiazoles containing carbonyl/sulfonyl tetrahydrohydropyridine moiety. In the current investigation, we have synthesized many analogs maintaining the 1,3,4-oxadiazole-1,2,3,6-tetrahydropyridine ring and having modifications on the oxadiazole, phenyl ring. in order to compare their biological activities. The starting compound was 4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine obtained by the reaction of isonicotinic acid hydrazide and triethyl orthoacetate/orthobenzoate which were heated under reflux for 24 h. O-mesitylene sulfonyl hydroxylamine (MSH) was used to prepare the N-amino salt as an aminating agent. Mesitylene sulfonyl chloride was added with stirring to a solution of ethylacetohydroxymate and triethylamine in dimethylformamide at 0o C. Hydrolysis of this compound with the mixture of p-dioxane- 70% perchloric acid and allowing them to react for 45 min, gave a white solid of MSH. 4-(5-Methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine was reacted with MSH in dichloromethane to produce 1-amino-4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine mesitylenesulfonate. Reaction of the amino salt with substituted acid chlorides/sulfonyl chlorides in anhydrous tetrahydrofuran containing triethylamine gave stable ylides. This was followed by reduction with Sodium borohydride in absolute ethanol, which furnished the target compounds 1-(substituted phenylcarbonyl/sulfonylamino)-4-(5-methyl/phenyl-1,3,4-oxadiazole)-1,2,3,6-tetrahydropyridine. The biological activities of these compounds were evaluated in vitro on MCF-7 breast cancer cell lines. The novel compounds displayed moderate cytotoxicity. This research was supported by NIH/RCMI Grant (RCMI) # G12 RR03020 and Pharmaceutical Research Center NIH/NCRR grant 1 C06 RR12512-01.
Abstract 4673: EZH2 as a therapeutic target in glioblastoma: a cellular and molecular study
Authors: Javier de la Rosa, Marta Iraburu, Gabriel Gallo-Oller, Alejandro Urdiciain, Xing Fan, Mehdi H. Shahi, Bárbara Meléndez, Juan A. Rey, Miguel A. Idoate, Javier S. Castresana
Journal: Cancer Research (2017)

Abstract Glioblastoma is the most common and deadliest malignant brain tumor in adults. It is currently treated with a combination of surgery, radiotherapy and chemotherapy with temozolomide (TMZ). Resistance to TMZ is a challenge in the treatment of this type of brain cancer. Epigenetic modulation is a new possibility to be tested against glioblastoma. Inhibition of EZH2, a histone methyltransferase (H3K27met3) which is overexpressed in cancer cells, leading to angiogenesis and metastasis, might be a new strategy to treat this tumor. In this work, the EZH2 inhibitor DZNeP was tested in A172 glioblastoma cells and in A172-TMZ-resistant glioblastoma cells. Inhibition of cell proliferation, cell adhesion, colony formation, and cell migration was noted in A172 and A172-TMZ-resistant glioblastoma cells after DZNeP treatment. DZNeP also decreased EZH2 expression, and increased the expression of its target genes (E-cadherin and TIMP3), which might probably contribute to inhibiting the development of a cancer metastatic phenotype. Finally, DZNeP negatively regulated the TGFβ pathway: the expression of receptors involved in this pathway (TGFβR1 and TGFβR2) was decreased, and the expression of inhibitors of this pathway (BAMBI, SMAD6 and SMAD7) was increased. In order to support the results obtained by qRT-PCR about the TGFβ1 pathway, protein expression of SMAD2 and PSMAD2 was analyzed by Western blot. The ratio between PSMAD2/SMAD2 decreased in cells treated with DZNeP, which supports the possible therapeutic effect of this drug against the TGFβ pathway, as PSMAD2 is a negative prognostic marker in glioblastoma. In conclusion, we propose that inhibition of EZH2 might be considered as a therapeutic strategy against glioblastoma. Citation Format: Javier de la Rosa, Marta Iraburu, Gabriel Gallo-Oller, Alejandro Urdiciain, Xing Fan, Mehdi H. Shahi, Bárbara Meléndez, Juan A. Rey, Miguel A. Idoate, Javier S. Castresana. EZH2 as a therapeutic target in glioblastoma: a cellular and molecular study [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 4673. doi:10.1158/1538-7445.AM2017-4673
Abstract 4360: Epigenetic alteration at HBV integrants is associated with methylation at flanking human genome
Authors: Yoshiyuki Watanabe, Ritsuko Oikawa, Hiroyuki Yamamoto, Fumio Itoh
Journal: Cancer Research (2017)

Abstract Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis. Citation Format: Yoshiyuki Watanabe, Ritsuko Oikawa, Hiroyuki Yamamoto, Fumio Itoh. Epigenetic alteration at HBV integrants is associated with methylation at flanking human genome [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 4360. doi:10.1158/1538-7445.AM2017-4360
Abstract 2879: Dj-1 confers maintenance of stemness and radioresistance by regulating EGFRvIII expression in glioma stem cells
Authors: Myung-Jin Park, Jeong-Yub Kim, Hee-Jin Kim, Ji-Soo Kim, Jeong-Chul Kim, Dea-Hee Lee, Yoo-Jin Na
Journal: Cancer Research (2017)

Abstract DJ-1 is involved in many key cellular processes including cell proliferation, transcriptional regulation, differentiation, oxidative stress protection, and mitochondrial function maintenance. Deregulation of DJ-1 has been implicated in the pathogenesis of many human diseases such as Parkinson's disease, amyotrophic lateral sclerosis, infertility, and cancer. DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in numerous cancer types. Alteration in expression of DJ-1 is associated with tumorigenesis in several types of cancers. Herein, we aimed to clarify the effect of DJ-1 on stemness and radioresistance of glioma stem cells (GSCs). Firstly, we found that the reduction in expression of DJ-1 in brain tumor tissues when compared with tumor adjacent normal brain tissues, as indicated by reduced DJ-1 staining. Knock-down of DJ-1 inhibited self-renewal activity of GSCs in vitro as evidenced by neurosphere formation, limiting dilution, and soft agar clonogenic assays. DJ-1 knock-down suppressed maintenance of stemness by suppressing the expression of Notch intracellular domain, Sox2, and phosphorylated STAT3 proteins. Intriguingly, DJ-1 knock-down inhibited the expression of EGFRvIII in GSCs which might be the cause of suppression of stemness pathways. In addition, knockdown of DJ-1 induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. Based on these data, we propose that DJ-1 could be considered as a crucial diagnostics and therapeutics target for malignant glioma. Note: This abstract was not presented at the meeting. Citation Format: Myung-Jin Park, Jeong-Yub Kim, Hee-Jin Kim, Ji-Soo Kim, Jeong-Chul Kim, Dea-Hee Lee, Yoo-Jin Na. Dj-1 confers maintenance of stemness and radioresistance by regulating EGFRvIII expression in glioma stem cells [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 2879. doi:10.1158/1538-7445.AM2017-2879
Faecal microbiota composition associates with abdominal pain in the general population
Authors: Fatemeh Hadizadeh, Ferdinando Bonfiglio, Meriem Belheouane, Marie Vallier, Sascha Sauer, Corinna Bang, Luis Bujanda, Anna Andreasson, Lars Agreus, Lars Engstrand, Nicholas J Talley, Joseph Rafter, John F Baines, Susanna Walter, Andre Franke, Mauro D'Amato
Journal: Gut (2017)

We read with great interest the recent communication by Simren et al ,1 reporting a correlation between visceral hypersensitivity and GI symptom severity in functional GI disorders (FGID). Previously, it has been shown that visceral hypersensitivity can be modulated or even induced in animal models, by altering the composition of their gut microbiota with antibiotics or faecal transplantation from IBS donors.2 3 Hence, while a direct link between gut microbiota composition and visceral pain may need to be conclusively established, this holds great potential for translational exploitation in the treatment of IBS and other FGID. Thus far, the potential association between microbiota and abdominal pain in humans has only been investigated in one study that included 15 individuals.4 For this purpose, we studied 159 individuals (average age 59.1, 39.6% men) from the Swedish Population-based Colonoscopy (PopCol) cohort, previously described and with faecal microbiota 16S sequencing data and daily recordings of abdominal pain (number of episodes, duration and intensity) collected over the same period (7.41±7.91 days).5–7 Among these, 52 individuals (assigned to the case group) reported at least one episode …
Abstract 4050: Multifaceted targeting of drug-resistant EGFR+ and HER2+ breast tumors
Authors: Brian K. Law, Mary E. Law, Renan B. Ferreira, Mengxiong Wang, Bradley J. Davis, Ronald K. Castellano, Coy D. Heldermon
Journal: Cancer Research (2017)

Abstract Unmet needs in the breast cancer field include the development of effective treatments for 1) drug-resistant HER2+ breast cancers, 2) Triple-Negative (HER2-, ER-, PR-) Breast Cancers (TNBCs), and 3) Inflammatory Breast Cancers (IBCs). Treatment-refractory HER2+ tumors retain HER2 expression after acquiring drug resistance, and large fractions of TNBCs and IBCs overexpress either HER2 or EGFR. Thus, drugs that selectively kill breast tumors that overexpress EGFR or HER2 could benefit patients suffering from these three classes of treatment-refractory tumors. Our team has identified a class of compounds termed Disulfide bond Disrupting Agents (DDAs) that selectively kill cancer cells that overexpress HER2 or EGFR. DDA-mediated cancer-selective cytotoxicity results from A) downregulation of the EGFR/HER2/HER3 proteins, B) inactivation of the Akt oncogene, and C) activation of the Unfolded Protein Response (UPR). Importantly DDAs only elicit these responses in cancer cells that overexpress EGFR or HER2. DDAs exhibit striking anticancer activity in human HER2+ xenograft tumors grown orthotopically in mice, with no evidence of toxicity. DDAs function through mechanisms distinct from those of HER2 specific monoclonal antibodies and tyrosine kinase inhibitors, and biochemical studies indicate that DDAs are complementary with Lapatinib with respect to blockade of HER2 driven proliferative and survival signaling. Current efforts are directed toward identifying mechanism-based drugs that synergize with DDAs to potentiate HER1-3 downregulation, Akt inhibition, and UPR, and to kill HER2+/EGFR+ patient-derived xenograft tumors that are refractory to current therapies. Citation Format: Brian K. Law, Mary E. Law, Renan B. Ferreira, Mengxiong Wang, Bradley J. Davis, Ronald K. Castellano, Coy D. Heldermon. Multifaceted targeting of drug-resistant EGFR+ and HER2+ breast 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 4050. doi:10.1158/1538-7445.AM2017-4050
Abstract 3353: An epigenetic biomarker panel in HPV related oropharyngeal squamous cell carcinoma
Authors: Shuling Ren, Daria A. Gaykalova, Theresa Guo, Zubair Khan, Mizuo Ando, Sunny Haft, Joseph A. Califano
Journal: Cancer Research (2017)

Abstract HPV related head and neck squamous cell carcinoma (HNSCC) is known to occur in a separate patient population in comparison to tobacco related HNSCC, and also exhibits less mutational, genetic, and chromosomal alterations, and a different composition of epigenetic alterations. In particular, HPV is present in up to 70% of oropharyngeal squamous cell carcinoma (OPSCC), and is driving the increase in incidence rates of OPSCC. Given the precedent for successful screening for cervical cancer, it is attractive to consider similar population based screening for HPV related OPSCC. Here, we developed an epigenetic biomarker panel that can be combined with high risk HPV DNA detection with potential utility in screening. We performed high throughput qMBD-seq analysis on 50 primary HPV positive OPSCC samples and 25 UPPP normal samples. Subsequently, we performed an outlier analysis and ranking strategy of 100 bp segmented regions within this discovery cohort and defined 20 differentially methylated regions to be used as biomarkers for detection. Simultaneously, we validated these 20 biomarker candidates using TCGA methylation array dataset and found that the methylation levels of these 20 candidates in HPV positive OPSCC were significantly higher than those in normal samples. Moreover, we created QMSP assays for these genes, and validated EMBP1 and KCNA3 in a separate validation cohort including tissue and saliva from 46 HPV related OPSCC and 25 normal controls. The sensitivity and specificity values for EMBP1, KCNA3 or both in tissue and saliva are shown. EMBP1 has a high sensitivity in tissue and a high specificity in saliva, while KCNA3 has a high specificity in both tissue and saliva. A panel including both genes has an extremely high sensitivity. Ultimately, we defined a panel of two differentially methylation regions that has a high sensitivity in tissue. This study might serve as a diagnostic biomarker development trial for HPV OPSCC detection with potential application for development of a population based screening test. Sensitivity and specificity for HPV related OPSCC in tissue and salivaTissueTissueSalivaSalivaGeneSensitivitySpecificitySensitivitySpecificityEMBP197.7%83.3%13.3%94.7%KCNA376.7%92.0%13.3%94.7%EMBP1&amp; KCNA3100.0%84.0%13.0%84.2% Citation Format: Shuling Ren, Daria A. Gaykalova, Theresa Guo, Zubair Khan, Mizuo Ando, Sunny Haft, Joseph A. Califano. An epigenetic biomarker panel in HPV related oropharyngeal squamous cell carcinoma [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 3353. doi:10.1158/1538-7445.AM2017-3353
Abstract 5675: A novel PI3K inhibitor suppresses tumor progression by immune modulation
Authors: Zusheng Xu, Yangtong Lou, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou
Journal: Cancer Research (2017)

Abstract Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors have shown anti-tumor efficacy in leukemia in the clinic and one such compound, idelalisib, was approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia (CLL) in 2014. A novel PI3Kδ inhibitor, YY-20394, was developed with specific selectivity against PI3Kδ and inhibited PI3Kδ expressing human tumor cells growth both in vitro and in vivo. In addition, our previous data have shown YY-20394 significantly inhibited primary tumor growth in immune-competent mice with 4T1 and CT26 tumors, as well as 4T1 lung metastasis with dose dependency. The anti-tumor efficacy of YY-20394 was largely mediated by T cells. More importantly, YY-20394 synergistically enhanced the anti-tumor efficacy of anti-PD-L1 antibody in CT26 model and achieved long-term immune memory which is specific for CT26 tumors, but not for unrelated A20 tumors. In vitro mechanistic studies showed YY-20394 significantly inhibited T cell differentiation into Treg both in mouse splenocyte and in human primary CD4+ T cells, and was especially potent inhibiting their IL-10 secretion in vitro. Analyses of tumors treated with YY-20394 reviewed that YY-20394 decreased the percentage of Treg in the tumor infiltrating leukocytes, as well as IL-10 secretion. It also showed some effects on the myeloid populations in the tumors. These data suggest the YY-20394, a novel PI3Kδ inhibitor, represents a promising and safe immune modulator and shows great potential as a cancer immuno-therapeutics. Citation Format: Zusheng Xu, Yangtong Lou, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou. A novel PI3K inhibitor suppresses tumor progression by immune modulation [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 5675. doi:10.1158/1538-7445.AM2017-5675