tbuckley/cabot-search huggingface dataset:
Risks of Medical Metaphors
Authors: Benjamin W. Frush, John Brewer Eberly
Journal: JAMA (2017)

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Abstract 3316: Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria
Authors: Yasuyuki Nakamura, Masayuki Tsuneki, Makoto Yamamoto, Hirofumi Arakawa
Journal: Cancer Research (2017)

Abstract Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. Mieap suppresses murine intestinal tumor via its mitochondrial quality control (1). Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer (2). To explore the role of the Mieap-regulated mitochondria quality control function in human colorectal cancer tissues, we examined the Mieap expression in primary colorectal cancer tissues by performing immunohistochemical analysis with anti-human Mieap antibody. Mieap expression was very low in normal colorectal epithelial cells, whereas the strong expression of the Mieap protein was detected in the hypoxic cell death regions of colorectal adenoma and adenocarcinoma, suggesting the role of Mieap in hypoxic cell death. Overexpression of Mieap in vitro induced large vacuole structures (MIV: Mieap-induced vacuole) in HCT116 colorectal cancer cells (Mieap-deficient colorectal cancer cells). MIV engulfed and degraded unhealthy mitochondria, leading to caspase-dependent cancer cell death. Re-expression of Mieap in HCT116 cells resulted in striking suppression of tumor growth in vivo. These results suggest that Mieap plays a critical role in hypoxic tumor cell death via lysosomal degradation of unhealthy mitochondria. (1) Tsuneki et al. Mieap suppresses murine intestinal tumor via its mitochondrial quality control. Sci. Rep. 5: 12472 (2015). (2) Kamino et al. Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer. Oncogenesis 5: e181 (2016). Citation Format: Yasuyuki Nakamura, Masayuki Tsuneki, Makoto Yamamoto, Hirofumi Arakawa. Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria [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 3316. doi:10.1158/1538-7445.AM2017-3316
International risk of yellow fever spread from the ongoing outbreak in Brazil, December 2016 to May 2017
Authors: Ilaria Dorigatti, Arran Hamlet, Ricardo Aguas, Lorenzo Cattarino, Anne Cori, Christl A Donnelly, Tini Garske, Natsuko Imai, Neil M Ferguson
Journal: Eurosurveillance (2017)

States in south-eastern Brazil were recently affected by the largest Yellow Fever (YF) outbreak seen in a decade in Latin America. Here we provide a quantitative assessment of the risk of travel-related international spread of YF indicating that the United States, Argentina, Uruguay, Spain, Italy and Germany may have received at least one travel-related YF case capable of seeding local transmission. Mitigating the risk of imported YF cases seeding local transmission requires heightened surveillance globally.
Abstract 344: Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate stem cells
Authors: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman
Journal: Cancer Research (2017)

Abstract The chondroitin sulfatases N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) and N-acetylgalactosamine 6-sulfatase (galactose 6-sulfatase, GALNS) remove the 4-sulfate and 6-sulfate groups of chondroitin sulfates. ARSB acts to remove 4-sulfate groups of chondroitin 4-sulfate (C4S) or dermatan sulfate, and GALNS acts to remove 6-sulfate groups of chondroitin 6-sulfate (C6S) or chondroitin 4,6-disulfate, as well as keratan sulfate. In human prostate cancer tissues, ARSB activity was markedly reduced and GALNS activity increased. By immunohistochemistry of malignant prostate tissue captured by laser microdissection and by assay of human prostate stromal and epithelial cell lines, ARSB was predominant in stromal cells of the extracellular matrix, whereas GALNS predominated in prostate epithelial cells. When ARSB was reduced by silencing in human prostate stem cells or GALNS was increased by overexpression in the stem cells, SHP2 binding to chondroitin 4-sulfate increased, leading to inhibition of phosphatase action and sustained phosphorylation of Erk1,2. Erk activation enabled increase in c-Myc binding to nuclear DNA and increased expression of DNMT 1a, 3a, and 3b. DNMT activation increased following ARSB silencing or GALNS overexpression, and was blocked by ERK inhibition. Increased DNMT activity led to the increased promoter methylation of DKK3, and the subsequent inhibition of nuclear β-catenin nuclear translocation and Wnt signaling. Decline in Wnt signaling was manifested by reduced TCF-LEF nuclear binding, and decline in the mRNA expression of c-Myc and GATA. Since c-Myc activation can lead to increased expression of cell cycle regulators, the changes in chondroitin sulfation mediated by sulfatases can lead to profound effects in cell proliferation. Hence, the modification of sulfatase activity, manifested as increased chondroitin 4-sulfate, provides the platform for an extensive extracellular-intracellular signaling network that can regulate phosphorylation, DNA promoter methylation, and proliferation, and affect development and malignant transformation. Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman. Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate 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 344. doi:10.1158/1538-7445.AM2017-344
Abstract 2872: Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib
Authors: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami
Journal: Cancer Research (2017)

Abstract Background The development of rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib. A significant relationship exists between the severity of a rash and survival in various cancers. However, whether erlotinib becomes distributed to the skin and whether its concentration is higher in a rash than in normal skin of treated cancer patients remains unknown. Here, using quantitative mass spectrometry imaging (qMSI), we successfully visualized the distribution of erlotinib in rashes and normal skin of patients with advanced pancreatic cancer receiving this drug. Methods We studied five patients with advanced pancreatic cancer who developed rashes after treatment with gemcitabine (1000 mg/m² by intravenous infusion for 30 minutes on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We biopsied both rashes and normal skin, and compared the distribution of erlotinib using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The plasma concentration of erlotinib was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Erlotinib concentrations in five patients were 2.55 ± 1.46 ng/mm3 in normal skin and 3.18 ± 1.53 ng/mm3 (mean ± SD) in rashes (p=0.123). In four out of five patients, the erlotinib concentration in rashes was higher than that in normal skin. The epidermis showed the strongest expression of EGFR in skin as judged by immunohistological staining. Erlotinib showed a greater tendency for distribution to the epidermis than subcutaneous tissue. There was no correlation between erlotinib plasma concentrations vs. concentrations in rashes or normal skin. Conclusions Using qMSI, we, for the first time, visualized the distribution of erlotinib in skin tissue of pancreatic cancer patients receiving erlotinib. We found a tendency for a higher concentration of erlotinib in rashes than in normal skin. A greater distribution of erlotinib to the epidermis than subcutaneous tissue suggests erlotinib may directly bind EGFR expressed in the epidermis. Citation Format: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami. Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib [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 2872. doi:10.1158/1538-7445.AM2017-2872
Gastric perforation by stiff guidewire in Danis stent assembly
Authors: Ajinkya Sonambekar, Devendra Desai
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We congratulate Escorsell et al.1 for undertaking a difficult study due to lack of adequate numbers for enrollment. As the first randomized control trial in this area, this study attempts to fill in an unmet need. The SX‐ELLA Danis stent (Ella CS, Hradec Kralove, Czech Republic) has been reported to be widely successful with only a few complications, including esophageal ulcerations, failed deployment, bronchial compression, and stent migration.2 Even the index study1 reports self‐expanding metal stent‐related side effects in <10% of subjects. We would like to share our experience of a gastric perforation due to the Danis stent. This is first such case in the literature, and we attribute this to the Ultra Stiff guide wire used to deploy this stent. An octogenarian man with decompensated cryptogenic cirrhosis presented to us with hematemesis and hypotension. He was admitted and fluid resuscitation was initiated, along with intravenous somatostatin (later terlipressin), pantoprazole, ceftriaxone, and later inotropes. He received nine packed red cells, fresh frozen plasma, and cryoprecipitate. An upper gastrointestinal endoscopy revealed bleeding from esophageal varices. Bleeding was refractory to endoscopic variceal band ligation and variceal histacryl glue injection. We decided to deploy an SX‐ELLA Danis stent. The guide wire was placed endoscopically, and the stent was deployed uneventfully. A repeat endoscopy confirmed hemostasis. A postprocedure skiagram revealed that the stent was in situ, but there was air under the diaphragm (Fig. 1); there was no pneumomediastinum. Intra‐abdominal pigtail catheters were inserted bilaterally under ultrasonography guidance because the patient was unfit for surgery. He succumbed to multiorgan dysfunction the following morning.Figure 1: Skiagram showing self‐expanding metal stent in situ, with air under the right dome of the diaphragm.In our patient, we placed the guidewire in the antrum under endoscopic guidance. We did not have any technical difficulty in placing the stent. There were no ulcers in visualized mucosa. The stiff guide wire used for stent deployment is the only plausible explanation we have for the gastric perforation. Because Danis placement is usually done at the bedside, without radiological assistance, we recommend that the stiff guide wire enclosed in the package be avoided until further evidence regarding its safety is available.
Abstract 3454: Autophagy governs tumorigenic effects following mitotic slippage
Authors: Karen C. Crasta, Bing Cheng, Ke Guo
Journal: Cancer Research (2017)

Abstract Antimitotic drugs are often administered as first-line chemotherapy in several malignancies. However, their clinical success is often limited by acquired chemoresistance and disease relapse. The anti-proliferative basis of these drugs is induction of mitotic arrest culminating in cell death. Mitotic slippage occurs when cells exit mitosis and “slip” into interphase without chromosome segregation and cytokinesis. Little is known about how cells post-slippage influence outcome of treatment. Here, we demonstrate that post-slippage cells exhibit paracrine pro-tumourigenic potential following senescence and senescence-associated secretory phenotype development. This occurs in an autophagy-p53 axis-dependent manner, with autophagic inhibition in post-slippage cells bypassing senescence and leading to cell death. Indeed, the autophagy inhibitor Chloroquine and microtubule poisons synergistically inhibited tumour growth in mice. Hence, regimens targeting the senescence phenotype could provide a potential effective combinatorial strategy with antimitotic drugs. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment. Citation Format: Karen C. Crasta, Bing Cheng, Ke Guo. Autophagy governs tumorigenic effects following mitotic slippage [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 3454. doi:10.1158/1538-7445.AM2017-3454
Abstract 862: Atypical protein kinase c inhibitors can repress epithelial to mesenchymal transition (type III) in malignant melanoma
Authors: Wishrawana Sarathi Ratnayake, Mildred Acevedo-Duncan
Journal: Cancer Research (2017)

Abstract Melanoma is a type of cancer occurs in melanocytes. Approximately 90% of melanoma occurs in skin (cutaneous melanoma) but can rarely arise from the mucosal surfaces or areas which neural cells migrate. Examples are eye, intestine and mouth [Eur. J. Cancer, 69: 39-42 (2016)]. 76,380 of new cases and 10,130 number of deaths are expected in 2016 in the USA due to melanoma [http://seer.cancer.gov/statfacts/html/melan.html (11/05/2016)]. Atypical PKCs contains two structurally and functionally distinct isozymes in human which are PKC-ι (iota) and PKC-ζ (zeta). They are believed to be involved in cell cycle progression, tumorigenesis, cell survival and cell migration. We believe that atypical PKCs play an important role in cell motility of melanoma by involving the signaling pathways which induces EMT-type III (Epithelial to Mesenchymal Transition). In normal melanocytes, PKC-ζ was found in low levels and PKC-ι was not detected. But both proteins are detected in very high levels in malignant melanoma [Melenoma Res. 12:201-209 (2002)]. In the current study, we have investigated the effects of novel atypical PKC inhibitors [4-(5-amino-4-carbamoylimidazol-1-yl)-2, 3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) which is specific to PKC-ι and 8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid (Compound-50) which is specific to PKC-ζ on the cell proliferation, apoptosis and cell migration of two malignant melanoma cell lines (SK-MEL-2 and MeWo) compared to a normal melanocyte cell line (PCS-200-013). We showed that both inhibitors can decrease the levels of total and phosphorylated levels of PKC-ζ and PKC-ι. Furthermore, both inhibitors increased the levels of E-cadherin and decreased the levels of Vimentin which is a mesenchymal marker associated with EMT. Treatments with inhibitors altered the levels of CD44, a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, migration and tumor cell homing during metastasis. These results suggest that both PKC-ι and PKC-ζ are involved in signaling pathways which upregulate EMT and which can be effectively suppress using ICA-1 and Compound-50. Furthermore we established that treatment with ICA-1/Compound-50 induced apoptosis as shown by increasing Caspase-3 levels and decreasing Bcl-2 levels. Citation Format: Wishrawana Sarathi Ratnayake, Mildred Acevedo-Duncan. Atypical protein kinase c inhibitors can repress epithelial to mesenchymal transition (type III) in malignant melanoma [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 862. doi:10.1158/1538-7445.AM2017-862
Abstract 2196: SDF-1/CXCR4 axis-mediated tumor-tropism of monocyte membrane-coated nanoparticles
Authors: Yi-Nan Li, Chien-Wen Chang, Chi-Shiun Chiang
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages are one of the most abundant infiltrating cells in solid tumors. These cells are originated from the bone marrow and circulating in peripheral blood. Through the specific chemoattractant released by the tumor cells or stromal cells, bone marrow-derived monocytes (BMDMs) are able to accumulate at the tumor site by their corresponding receptors. In this study, we utilized the characteristics of tumor-tropism of BMDMs on a nanoparticle-based drug delivery system. We hypothesized that the cellular membrane of BMDMs can provide nanoparticle protection from the mononuclear phagocyte system and the chemokine receptor on the membrane can enhance the tumor-tropism of the nanoparticles. To prove the hypothesis, the cellular membrane was extracted from BMDMs and then coated on the drug-loaded nanoparticles. We also found that the expression of chemokine receptor CXCR4 on the bone BMDMs can be induced following the stimulation of tumor conditioned medium. The tumor targeting effect of the monocyte membrane-coated nanoparticles is diminished against SDF-1 knockdown tumor cells. These results indicate that the SDF-1/CXCR4 axis is contributed to the tumor-tropism of the monocyte membrane-coated nanoparticles toward astrocytoma cell line, ALTS1C1, and this effect can be boosted by the stimulation of tumor conditioned medium. In conclusion, we established a nanoparticle-based drug delivery platform against brain tumor with the cellular membrane coating technology and maximized the effect of tumor-targeting by tumor conditioned medium stimulation. Citation Format: Yi-Nan Li, Chien-Wen Chang, Chi-Shiun Chiang. SDF-1/CXCR4 axis-mediated tumor-tropism of monocyte membrane-coated nanoparticles [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 2196. doi:10.1158/1538-7445.AM2017-2196
Abstract 2716: A multi-parameter assay for the detection of rare malignant cells in classical Hodgkin lymphoma
Authors: Lance U'Ren, David Wu, Jonathan R. Fromm, Jackie Stilwell, Eric Kaldjian
Journal: Cancer Research (2017)

Abstract Background: Classical Hodgkin Lymphoma (CHL) ranks among the most frequently occurring lymphomas and is marked by Hodgkin and Reed-Sternberg (HRS) cells, frequently multi-nucleated neoplastic cells that are derived from germinal center B cells. The genetic alterations involved in the pathogenesis of this lymphoma have been difficult to study because HRS cells are rare and are surrounded by robust, non-neoplastic infiltrate, therefore they frequently represent less than 0.1% of cells within involved lymph nodes. Consequently, methods that isolate these rare cells are required to understand pathobiology of this lymphoma. We used the AccuCyte® - CyteFinder® system (RareCyte) to develop a method for detection and isolation of HRS cells. Methods: A 6-parameter immunofluorescence assay was designed to identify HRS cells that included HRS markers (CD40, CD30, CD15), CD3, combined CD20/CD14 and a cell membrane permeability viability dye. The assay was tested using the KMH2 Hodgkin lymphoma cell line spiked into PBMC and transferred to well slides for imaging by CyteFinder. This instrument utilizes 6-color scanning microscopy coupled with predefined algorithms to identify rare cell populations. The assay was then applied to a frozen fine needle aspirate (FNA) sample taken from the lymph node of a patient with histologically confirmed CHL. The FNA sample was thawed, prepared into a suspension, stained and analyzed as above. Cells identified with HRS phenotype were individually retrieved using the integrated CytePicker module. PCR of framework regions of the immunoglobulin heavy chain gene (IGH) was performed on single HRS cells (InvivoScribe) to assess clonality. Results: Of ~200 KMH2 cells spiked into blood, the assay identified 180 cells (90%) with the correct HRS phenotype. HRS phenotype cells were identified in the patient lymph node FNA sample. Two individual cells analyzed by IGH framework region PCR demonstrated identical size PCR products, indicating clonality of the B cell receptor rearrangement. Conclusion: A multi-parameter assay was successfully developed for identifying rare HRS cells with the CyteFinder system. Cells with HRS phenotype in a lymph node FNA sample were demonstrated to have clonal IGH rearrangements, demonstrating that actual HRS cells were identified. This method may be a useful tool for the diagnosis of CHL by identification of rare HRS cells from FNA specimens, as well as to investigate the molecular genomics of CHL. Citation Format: Lance U'Ren, David Wu, Jonathan R. Fromm, Jackie Stilwell, Eric Kaldjian. A multi-parameter assay for the detection of rare malignant cells in classical Hodgkin lymphoma [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 2716. doi:10.1158/1538-7445.AM2017-2716