tbuckley/cabot-search huggingface dataset:
Abstract 4407: Inhibition of STAT3 in primary trastuzumab-resistant HER2-positive cells leads to decrease cell viability
Authors: Xousaen M. Helu, Alfida Fernandez, Daisy D. De Leon
Journal: Cancer Research (2016)

Abstract Breast Cancer is the second leading cause of cancer related death in women. Approximately, 20%-30% of breast cancer patients overexpress Human Epidermal Growth Factor Receptor 2 (HER2). HER2 Is a Tyrosine Kinase receptor involved in proliferation and survival and its overexpression makes it a good target for patients with HER2 positive breast cancer. Trastuzumab (TRA) is a recombinant monoclonal antibody that binds HER2 receptor and inhibits its signaling. Unfortunately, clinical studies have demonstrated that 30% of patients that overexpress HER2 do not respond to Trastuzumab treatment. Therefore, understanding the molecular mechanisms underlying Trastuzumab resistance is essential to develop new therapies to treat these breast cancer patients. Previous studies in our lab demonstrated that a decrease in cell growth of HER2 overexpressing cells occurred when IGF2 and HER2 were inhibited. Nevertheless, these cells overcame the growth inhibition and the resulting proliferative growth coincided with an increase in STAT3 activation. STAT3 is a transcription factor that promotes cell proliferation and can regulate apoptosis in cancer cells. These findings lead us to hypothesize that blocking STAT3 together with IGF2 and HER2 will inhibit proliferation and cell viability of Trastuzumab resistant breast cancer cells. We treated Trastuzumab-resistant HER2 positive JIMT1 cells with HER2, IGF2, and/or STAT3 inhibitors. After 24 hours of treatment, there was a marked difference in cell morphology observed between the treatment groups. Cell viability was measured using WST-1, a reagent that measures mitochondrial activity. A significant decrease in cell viability was observed when cells were treated for 24 hours with a commercially available STAT3 inhibitor (Sttatic). There was no difference between the treatment groups when STAT3 was inhibited by Stattic or when STAT3 was inhibited in combination with IGF2 and/or HER2 inhibitors. These findings suggest that in Trastuzumab-resistant HER2 positive JIMT1 cells, STAT3 activation overcomes the inhibition of the HER2 and IGF2 proliferation pathways resulting in cell death prevention. Our study demonstrate that Trastuzumab-resistant HER2 positive JIMT1 cells can activate STAT3 as an alternative pathway to evade apoptosis and promote chemoresistance. Our data also illustrate the challenge of treating cancer based on single therapies since tumors have many alternative pathways to promote growth. Citation Format: Xousaen M. Helu, Alfida Fernandez, Daisy D. De Leon. Inhibition of STAT3 in primary trastuzumab-resistant HER2-positive cells leads to decrease cell viability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4407.
Abstract 3027: Dual inhibition of PKC and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
Authors: Guillaume Carita, Estelle Frisch Dit Leitz, Ahmed Dahmani, Chloe Raymondie, Nathalie Cassoux, Sophie Piperno-Neumann, Fariba Némati, Ensar Halilovic, Sebastien Jeay, Andrew Wylie, Caroline Emery, Sergio Roman-Roman, Marie Schoumacher, Didier Decaudin
Journal: Cancer Research (2016)

Abstract Uveal melanoma (UM), although rare in incidence, is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified and therefore novel therapeutic approaches are urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway. This has led to the use of PKC inhibitors as a rational targeting strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models, several PKC inhibitor-based combination studies were performed using the PKC inhibitor AEB071 (Sotrastaurin). When combined with AEB071, the targeted agents CGM097 (p53-MDM2 inhibitor), RAD001 (Everolimus, mTORC1 inhibitor) and MEK162 (Binimetinib, a MEK inhibitor) demonstrated greater activity in the UM patient-derived xenograft models than their activity as single agents. Importantly, tumor regressions were observed in several UM models with AEB071 + RAD001 and AEB071 + CGM097 co-treatments. Follow-up in vitro studies in UM cell lines using AEB071 combined with either CGM097 or RAD001 provided a more detailed mechanistic understanding of their combination activity and confirmed their ability to induce cell death. Together, these preclinical studies reveal that combining PKC and p53-MDM2 inhibitors or PKC and mTORC1 inhibitors may provide significant clinical benefit for patients with UM. Citation Format: Guillaume Carita, Estelle Frisch Dit Leitz, Ahmed Dahmani, Chloe Raymondie, Nathalie Cassoux, Sophie Piperno-Neumann, Fariba Némati, Ensar Halilovic, Sebastien Jeay, Andrew Wylie, Caroline Emery, Sergio Roman-Roman, Marie Schoumacher, Didier Decaudin. Dual inhibition of PKC and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3027.
The safety and efficacy profiling of T-DM1 treatments of metastatic breast cancer patients
Authors: Tsutomu Iwasa, Kazuhiko Nakagawa, Junji Tsurutani, Satomi Nishida, Yoshifumi Komoike, Yukihiko Hashimoto, Tatsuya Azumi, Wataru Shinzaki
Journal: Annals of Oncology (2015)
Abstract 3739: Efficacy of CD46-mediated Ad5/35 chimeric adenoviral gene therapy in colorectal cancers
Authors: Young Seok Cho, Hung Manh Do, Sang-Jin Lee, Silvio Hemmi, Young-Eun Joo, Chaeyong Jung
Journal: Cancer Research (2016)

Abstract CD46 is a complement inhibitor membrane cofactor protein and also acts as a receptor for certain pathogenic microbes, including group B denovirus (Ad). Whereas many Ads infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancers preventing effective therapeutics of Ad-based therapies. There have been increasing numbers of studies in cancer gene therapy by modification of Ad fiber knobs to utilize more ubiquitously expressed CD46. However, very limited information is available on expression status of CD46 in many cancers. Our tissue microarray data demonstrated that CD46 was generally overexpressed to cancers from prostate and colon. To seek the evidence whether colorectal cancers (CRC) are good target for Ad-mediated gene therapy, chimeric Ad5 vectors that are capable of targeting CD46 were employed. CD46-ovrexpressed cells showed significantly higher response not only to Ad5/35-GFP but to Ad5/35-TK/GCV suicide therapy. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and cell killing, demonstrating that HCT-116, DLD-1, and Caco-2 cells are highly responsive. Furthermore, injection of Ad5/35-TK/GCV caused significantlyhigher anti-cancer effects in nude mice bearing CD46-overexpressed cancer cells compared to mice with mock cells. Using 80 selected CRC, immunohistochemical studies showed that there is inverted correlation between CD46 expression and clinico-pathological parameters in terms of differentiation, invasion, metastasis, T stage, and survival, suggesting that adenoviral gene therapy may not be as effective to the patients with highly advanced colorectal cancers. Taken altogether, our study demonstrated that CD46 is generally overexpressed in CRC in which group B-based adenoviral gene therapy seems to be suitable approach but careful consideration needs to be given to select cancer types and cancer status for effective cancer gene therapies. Citation Format: Young Seok Cho, Hung Manh Do, Sang-Jin Lee, Silvio Hemmi, Young-Eun Joo, Chaeyong Jung. Efficacy of CD46-mediated Ad5/35 chimeric adenoviral gene therapy in colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3739.
Abstract 1941: Plasma levels of miRNA-155 as a powerful diagnostic marker for dedifferentiated liposarcoma
Authors: Aleksandar Boro, David Bauer, Walter Born, Bruno Fuchs
Journal: Cancer Research (2016)

Abstract PURPOSE: Atypic lipomatous tumors (ALT) and dedifferentiated liposarcomas (DDLS) are closely related liposarcoma subtypes, often difficult to distinguish but they exhibit an entirely different clinical outcome. Recently discovered regulatory functions of miRNAs in liposarcoma progression prompted us to investigate miRNAs as potential diagnostic biomarkers in liposarcoma with a main focus on circulating miRNAs for fast and reliable differential diagnosis. PATIENTS AND METHODS: Tumor and blood samples of 35 patients with lipomatous lesions collected between June 2011 and September 2014 were analyzed by qRT-PCR. They included 10 lipomas, 7 ALT, 5 DDLS and 13 myxoid liposarcomas (MLS). Ten samples of normal fat tissue and blood from 20 healthy volunteers were used as controls. RESULTS: A meta-analysis of public data on miRNA expression in liposarcoma revealed 9 miRNAs with potential diagnostic power. Out of these, miRNA-155 was found significantly elevated in the circulation of DDLS patients as compared to the plasma levels detected in all other liposarcoma subtypes and in healthy subjects. miRNA-155 levels in the plasma samples correlated significantly (r = 0.41,p = 0.02) with those in corresponding tumor extracts. This correlation was even more pronounced in an analysis of plasma and tumor extracts of malignant liposarcoma subtypes alone (r = 0.51,p = 0.02). Receiver operating characteristic analysis indicated that plasma miRNA-155 levels have a high diagnostic accuracy for distinguishing DDLS from healthy subjects (AUC = 0.91,p = 0.005) and from lipomas (AUC = 0.86,p = 0.02), MLS (AUC = 0.92,p = 0.006) and most importantly ALT (AUC = 0.91,p = 0.01) patients. CONCLUSION: In conclusion, this study identified miRNA-155 as a first blood biomarker for the differential diagnosis of DDLS. Citation Format: Aleksandar Boro, David Bauer, Walter Born, Bruno Fuchs. Plasma levels of miRNA-155 as a powerful diagnostic marker for dedifferentiated liposarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1941.
Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy
Authors: Eunji Jang, Eunjung Kim, Hye-Young Son, Eun-Kyung Lim, Hwunjae Lee, Yuna Choi, Kwangyeol Park, Seungmin Han, Jin-Suck Suh, Yong-Min Huh, Seungjoo Haam
Journal: Biomaterials (2016)
Geographic practice patterns in the selection of adjuvant dose dense (DD) chemotherapy among stage 1 breast cancer (BC) patients.
Authors: William J. Hrushesky, Michael Baum, Charles L. Bennett, Kevin Knopf, Dinah Faith Q. Huff
Journal: Journal of Clinical Oncology (2016)

126 Background: Oncology Analytics (OA) reviewed drug pre-authorization requests amongst populations with similar demographic features. Small stage I, node-negative, margin-free BC may be treated by observation, hormone therapy or adjuvant chemotherapy. If chemo is used, either standard or DD schedules may be requested. Patient age, HER2 status, and ER expression affect the choice of treatment. Methods: We analyzed data from oncology drug preauthorization requests for BC protocols submitted by providers in FL, GA and TX from October 1, 2013 through September 30, 2015. Pearson chi-square was used to test for association at 95% CL. Risk was bifurcated by consideration of age, putative ER/PR status, and HER2 status. High-risk patients are those with putative ER/PR(-) status and/or Her2(+) status and/or younger than 50 years old. Results: Requests for standard and DD chemotherapy are related to the risk characteristics of the tumor. Oncologists in GA/TX prescribed a greater proportion of adjuvant chemotherapy for stage I BC patients than oncologists in FL (13.13% GA/TX vs 9.97% FL;p = 0.001). About 40% of all stage 1 chemotherapy requests are for dose-dense chemotherapy. Patients with high risk BC have a higher chance of getting dose dense chemotherapy than the low risk subgroup. FL oncologists have a higher likelihood of prescribing dose-dense chemotherapy than GA/TX oncologists (82% FL vs 65% TX p &lt; 001) if the BC risk is high, whereas the opposite is true if the patient is low risk (8% FL vs 17% GA/TX, p = 0002). Conclusions: While these geographical differences may be random, it may also be relevant that OA has worked in Florida for six, Georgia and Texas for two years. This suggests that patients with low risk disease are less likely to get the more toxic DD therapy if OA is in a market for a longer period of time.
What does it take to put an ugly fact through the heart of a beautiful hypothesis?
Authors: R. Brian Haynes MD
Journal: Annals of Internal Medicine (2009)

Thomas Huxley characterised “the great tragedy of Science” as “the slaying of a beautiful hypothesis by an ugly fact.” Unfortunately, when medical hypotheses are disproven, they act more like zombies than corpses, revived by the sorcerers of Mammon, aided and abetted by the inertia of medical practice.

Recent examples in diverse areas of clinical practice will likely suffer the problem of perseverance of beautiful but flawed hypotheses, so we are raising the alarm now. Three large trials in 2008 showed that intensive control of type 2 diabetes mellitus lacks benefits for patients and increases adverse effects1-3 (including one in this issue of Evidence-Based Medicine 4), and 2 trials showed that the self-monitoring of blood sugar in type 2 diabetes is not cost-effective5 and is associated with depression.6 Two trials have documented the lack of benefits of antiviral agents for Bell palsy (while confirming the benefits of corticosteroids).7 8 Many trials and meta-analyses have confirmed and reconfirmed the absence of benefits and presence of harmful effects of antioxidants for the prevention of cancer9 10 and cardiovascular disease.11

For each of these “slayings,” vested interests will undoubtedly try to make us forget that the justification for their promotions has been gored. For type 2 diabetes, …
The effect of mass mosquito trapping on malaria transmission and disease burden (SolarMal): a stepped-wedge cluster-randomised trial
Authors: Tobias Homan, Alexandra Hiscox, Collins K Mweresa, Daniel Masiga, Wolfgang R Mukabana, Prisca Oria, Nicolas Maire, Aurelio Di Pasquale, Mariabeth Silkey, Jane Alaii, Teun Bousema, Cees Leeuwis, Thomas A Smith, Willem Takken
Journal: The Lancet (2016)
Abstract 914: Sox10 regulates stem- and mesenchymal-like features in mammary cells
Authors: Christopher Dravis, Geoffrey M. Wahl
Journal: Cancer Research (2016)

Abstract To discover mechanisms that mediate the initiation and progression of aggressive and stem-like breast cancers, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor, Sox10. Here we report that Sox10 is specifically expressed in mammary cells that exhibit the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence, while its overexpression increases stem/progenitor activity. Intriguingly, we also discover that Sox10 overexpression elicits epithelial-to-mesenchymal transition (EMT) in mammary organoids in an FGF signaling-dependent manner. Further, modulation of Sox10 levels can induce sequential EMT, migratory, and clonogenic behaviors that strikingly resemble proposed mechanisms of metastasis. Consistent with these findings, we report that Sox10 is preferentially expressed in the most stem- and EMT-like triple negative breast cancer subtypes, which suggest that Sox10 may reprise these same functions during tumorigenesis. Indeed, we find that in an autochthonous mouse model of basal-like breast cancer, Sox10 is expressed at high levels and that these Sox10+ tumor cells exhibit characteristics that are similar to mammary cells in which Sox10 is ectopically expressed. Collectively, these results demonstrate a signaling mechanism through which stem and mesenchymal-like states are acquired in mammary cells, and indicate possible therapeutic targets to counter these functions in breast cancers for which targeted therapies are currently unavailable. Citation Format: Christopher Dravis, Geoffrey M. Wahl. Sox10 regulates stem- and mesenchymal-like features in mammary cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 914.
Defining a Research Agenda for Patient-Reported Outcomes in Surgery
Authors: Michael L. Pezold, Andrea L. Pusic, Wess A. Cohen, James P. Hollenberg, Zeeshan Butt, David R. Flum, Larissa K. Temple
Journal: JAMA Surgery (2016)

Identifying timely and important research questions using relevant patient-reported outcomes (PROs) in surgery remains paramount in the current medical climate. The inaugural Patient-Reported Outcomes in Surgery (PROS) Conference brought together stakeholders in PROs research in surgery with the aim of creating a research agenda to help determine future directions and advance cross-disciplinary collaboration.
Viande hachée de bœuf et salmonelloses humaines : synthèse des investigations de trois épidémies en France
Authors: S Haeghebaert, L Duché, C Gilles, B Masini, M Dubreuil, J C Minet, P Bouvet, F Grimont, E Delarocque Astagneau, V Vaillant
Journal: Eurosurveillance (2001)

La synthese des investigations de trois epidemies de salmonelloses en France de 1998 a 2000 confirme l’implication de la consommation de steaks haches de boeuf et souligne l’importance des mesures de prevention sanitaire.
Abstract 2794: Six-transmembrane epithelial antigen of prostate 4 (STEAP4): an important link between hypoxia, inflammation, nutrition and tumorigenesis in the intestine
Authors: Xiang Xue, Yatrik Shah
Journal: Cancer Research (2016)

Abstract Hypoxia occurred in the inflammatory foci can further increase the pro-inflammatory response. Moreover, inflammatory hypoxia is critical for altering tissue metabolism and nutritional response, which can further sustain the inflammation and drive tumorigenesis. However, the mechanisms that link hypoxia, nutrition, inflammation and tumorigenesis are not clear. Through genome-wide expression analysis we identified six-transmembrane epithelial antigen of prostate 4 (STEAP4) as a gene highly induced by hypoxia. STEAP4 is an oxidoreductase that regulates inflammatory stress, fatty acid, glucose and iron metabolism. Here we demonstrate that the increase in STEAP4 is dependent on epithelial HIF-2α in mouse models of colitis. Luciferase reporter assay and ChIP assay confirmed that STEAP4 is a HIF-2α target gene. Compared to normal healthy controls, the gene expression of STEAP4 was highly induced in tissues from colitis patients. Transgenic mice overexpressing GFP-tagged STEAP4 specifically in intestinal epithelial cells demonstrated that STEAP4 was expressed primarily on the plasma and mitochondrial membrane. Interestingly, these mice had no change in serum and tissue minerals except for a slight increase in intestinal iron, specifically mitochondrial iron, but no change in systemic iron levels. STEAP4 transgenic mice were highly susceptible to acute experimental colitis model. Moreover, STEAP4 was increased in human colorectal cancer (CRC) and predicts poor prognosis. Consistently, tumor numbers in the STEAP4 transgenic overexpression mice were increased compared to wild-type littermates in a colitis-associated CRC tumor model. Mechanistically, overexpression of STEAP4 increased oxidative stress and DNA damage in the intestine. In conclusion, we have identified a novel gene induced in colitis and CRC that could link hypoxia-induced metabolic changes, inflammation and cancer. Citation Format: Xiang Xue, Yatrik Shah. Six-transmembrane epithelial antigen of prostate 4 (STEAP4): an important link between hypoxia, inflammation, nutrition and tumorigenesis in the intestine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2794.
P-206 Efficacy and tolerance of a simplified combination of Streptozotocin and epi-adriamycin in metastatic foregut neuroendocrine tumor (NET)
Authors: L. Hirsch, C. Lepere, J.-N. Vaillant, S. Louafi, S. Pernot, B. Landi, A. Zaanan, J. Taieb, P. Rougier
Journal: Annals of Oncology (2015)
The New Antibiotic Mantra—“Shorter Is Better”
Authors: Brad Spellberg
Journal: JAMA Internal Medicine (2016)

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