bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect and mechanism of ikkβ on proliferation, apoptosis, and metastasis of breast cancer cells with different expression levels of leptin and its receptors.
Authors: Kong Yan , Dong Qian , Geng Cuizhi , Jiang Da 
Published: May 2020

e15592 Background: To investigate the effect and mechanism of IKKβ on proliferation, apoptosis, invasion and metastasis of breast cancer cells with different expression levels of leptin and ObR. Methods: IKKβ in breast cancer cells was knocked down via virus transfection technology. MTT, flow cytometry, cell scratch test and clone formation test were used to observe the effect of IKKβ on proliferation, apoptosis and metastasis of breast cancer cells with different expression levels of leptin and ObR. RT-PCR was used to detect the downstream genes expressions in IKKβ signaling pathway. Results: The expression levels of leptin and ObR in MDA-MB-231 cells were higher than those in MCF-7 cells. Lentivirus can successfully infect breast cancer cells in vitro and knock down the expression of IKKβ. Knocking down IKKβ reduced the viability of MDA-MB-231 cells, but had little effect on MCF-7, and had an effect on the cell cycle of both cells. After knocking down IKKβ, the apoptotic rate of MDA-MB-231 cells increased. There was no significant difference in the apoptotic rate of MCF-7 cells. The number of clones of MCF-7 and MDA-MB-231 cells decreased, and the difference was significant. The effect on MDA-MB-231 cells was more significant. The scratch mobility of MDA-MB-231 cells decreased significantly, with significant difference.After knocking down IKKβ, the expressions of leptin and ObR, IKBKG, P65 and HIF in MCF-7 cells were significantly decreased, and there was statistical significance. However, the above indicators were significantly increased in MDA-MB-231 cells. The expression level of IKBKG was increased significantly, whereas that of HIF did not differ significantly, as compared with that of control group. Conclusions: The proliferation, metastasis and apoptosis of MDA-MB-231 cells were inhibited after blocking the IKKβ pathway, while the proliferation of MCF-7 cells was inhibited, and the apoptosis did not change significantly. The difference between the two cells may be related to the different expression levels of leptin and ObR.After blocking the IKKβ signaling pathway, the expressions of genes related to the IKKβ signaling pathway in MDA-MB-231 cells were increased, whereas those in MCF-7 cells were decreased, which might be related to the different expression levels of leptin and ObR.After knocking down IKKβ, the expressions of HIF gene in MCF-7 cells were decreased, whereas those in MDA-MB-231 cell lines were not affected. It needs to be verified whether this difference is related to leptin and ObR.
Chick chorioallantoic membrane (CAM) assays as a model of xenografts derived from circulating cancer stem cells from breast cancer patients.
Authors: Pizon Monika , Schott Dorothea , Pachmann Ulrich A. , Pachmann Katharina , Schobert Rainer 
Published: May 2020

e15596 Background: Circulating cancer stem cells (cCSCs) are a rare fraction of circulating tumor cells with a profile of stemness, resistance to chemotherapy and the capacity to generate metastases. Patient-derived xenografts (PDX) are an increasingly noticed tool in oncology, providing biologically meaningful models of many cancer types, and potential platforms for the development of precision oncology approaches. Commonly, mouse models are used for the in vivo assessment of potential new therapeutic targets in cancers. However, given the high cost, time investment, and legal obligations of such animal models CAM assays are an attractive alternative. Methods: In this study, primary cultures from circulating cancer stem cells were established using sphere-forming assays. Subsequently, tumorspheres were transplanted onto the CAM membrane of fertilized chicken eggs to form secondary microtumors. Results: We have developed an innovative in vitro platform for cultivation of CSCs from peripheral blood of breast cancer patients. The number of tumorspheres increased significantly with tumor progression. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p < 0.05). Patients with multiple metastases had more tumorspheres compared to patients with single metastases (30 vs 60/100µl blood, p < 0.05). The number of tumorspheres was positively correlated with Ki-67, Her2 status and grade score in primary breast tumors. Tumorspheres showed self-renewal, growth potentials, invasion and differentiation in vivo. Their transplantation on CAM membranes resulted in the rapid formation of microtumors in many cases. These tumors pathologically closely resembled the primary tumor. The success rate of PDX was positively correlated with aggressiveness and proliferation capacity of the primary tumor. Conclusions: The number of tumorspheres cultured from peripheral blood of cancer patients and the success rate of establishing PDX directly reflect the aggressiveness and proliferation capacity of the primary tumor. A CAM-based PDX model using circulating cancer stem cells provides a fast, low-cost, easy to handle and powerful preclinical platform for drug screening, therapy optimization, and biomarker discovery.
Efficacy of telotristat ethyl: A peripheral tryptophan hydroxylase inhibitor that blocks serotonin biosynthesis against cultured liposarcoma, colon cancer, and cholangiocarcinoma cell lines.
Authors: Kliman Harvey J. , Ling Ivy S , Milano Kristin M 
Published: May 2020

e15602 Background: Serotonin (5-HT) is most often considered a neurotransmitter—but in reality its main function is to promote cell proliferation at the site of wound healing via platelet degranulation. We tested the hypothesis that blocking 5-HT production in cancer cells might lead to their death by exposure to a specific tryptophan hydroxylase (TPH) inhibitor: telotristat ethyl (TE). The advantage of this TPH inhibitor is that it does not cross the blood brain barrier and therefore can be used to treat peripheral cancers without danger of interfering with central nervous system 5-HT production. Methods: Three cancer cell lines were tested: liposarcoma (94T778), colon cancer (HT-29), and cholangiocarcinoma (TFK-1). The cells were grown with 0, 5, 15 and 30 µM TE, plated into four-chambered slides with an initial confluence of at least 30%, and cultured for 24-96 H. At the end of each 24 hour period slides were removed, washed, fixed, and stained with hematoxylin for density assessment. Experiments were performed in triplicate and repeated in at least three separate experiments. Cell confluence was determined under low power microscopic examination. Results: In the absence of TE the three cell lines increased their confluence from approximately 30% to 83±5.8% (94T778), 68±11% (HT-29), and 60±16% (TFK-1) over 96 H. When the 94T778 cells were exposed to increasing concentrations of TE their confluence decreased progressively. At a dose of 30 µM cell confluence at 24 H was 3±0%, at 48 H 0.3±0.6%, at 72 H 0±0%, and at 96 H 0±0%. For the HT-29 cells, cell confluence in the 30 µM TE groups were 12±8%, 3±3%, 7±5% and 2±1% at 24, 48, 72 and 96 H, respectively. For the TFK-1cells, cell confluence in the 30 µM TE groups were 7±3%, 20±14%, 17±14% and 24±16% at 24, 48, 72 and 96 H, respectively. Conclusions: Telotristat ethyl is a potent inhibitor of tumor cell line growth. However, the efficacy of this inhibition varies between cell lines. The liposarcoma cell line was most sensitive to TE, with the cholangiocarcinoma cell line being moderately impacted. The colon cancer cell line was intermediate between these two. The differences in response to TE may be related to the specific expression of TPH in any particular cell line, with cancers that are more dependent on 5-HT production being most impacted by TPH blockade. Just as ER PR positive breast cancers are sensitive to blockade of these receptors, TPH positive cancers may be successfully targeted by specific inhibition of the 5-HT biosynthetic pathway.
EIT PACMAN Study preliminary results: OncoSignal pathway analysis identifies actionable cancer targets.
Authors: Martin Patricia , Neerken Sigi , Van De Stolpe Anja , den Biezen-Timmermans Eveline , Akse Martijn , Ngocamus Maud , Nicotra Claudio , Eggermont Alexander M. , Van De Wiel Paul , Massard Christophe , Calvo Fabien M. 
Published: May 2020

e15606 Background: Precision medicine refers to tailoring of treatment to each individual patient, although identifying tumor driving signaling pathways (SP) that are functionally active is still a challenge. OncoSignal pathway tests quantitatively measure activity of SP such as estrogen receptor (ER), androgen receptor (AR), PI3K, MAPK, Hedgehog (HH), TGF-β, Notch on fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissue samples. OncoSignal pathway analysis aimed at assessing clinically actionable SP and retrospectively predicting targeted drug response on a series of patients’ (pts) samples from the MOSCATO trial run at Gustave Roussy. Methods: OncoSignal pathway analysis (ER, AR, PI3K, MAPK, HH, Notch, TGF-β) was performed blinded by Molecular Pathway Dx (Philips, Eindhoven) on metastatic tumor tissue samples from breast cancer (BC), prostate (PC), and high grade serous ovarian cancers (OC). Using Affymetrix expression array data from public GEO datasets, SP activity was analyzed in healthy prostate, breast, and ovarian tissue to define abnormal SP activity thresholds for tumor tissue pathway analysis. For each individual sample, SP alterations were considered tumor driving SP if sample SP activity exceeded the 95th percentile of SP activity within healthy tissue. Results by OncoSignal were also combined with clinical characteristics and molecular alterations identified in the MOSCATO trial. Results: Identified tumor driving SP were ER, AR, MAPK-AP1, HH, PI3K pathway in BC (n = 5), AR in PC (n = 30); AP1, Notch, TGFβ in OC (n = 17). OncoSignal identified clinically actionable tumor driving pathways in all BC samples (median tumor cellularity [MTC]: 40%, range 15-80%); 30/31 PC samples (MTC: 62%, range 25-90%), 16/17 OC samples (MTC 62%, range 15-80%). Actionable mutations were previously identified in 4/5 BC; 13/31 PC; 6/17 OC. Seven pts with BC and PC were treated with targeted therapy. OncoSignal pathway analysis correctly predicted response/resistance in 4 of these pts (57%). Conclusions: OncoSignal pathway analysis correctly identified SP activity alterations and predicted targeted drug response in this series of patients. OncoSignal will be further validated prospectively in precision medicine studies at Gustave Roussy in which patients are stratified for targeted treatment by mutation analysis.
Role of tafamidis in reducing the effect and progression of transthyretin amyloid cardiomyopathy.
Authors: Konda Raghunandan , Vadala David , Rafae Abdul , Isa Sakiru , Devarkonda Vishal , Kesari Kavitha , Kunadi Arvind 
Published: May 2020

e15612 Background: Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a rare, life-threatening, progressive and underdiagnosed cause of restrictive cardiomyopathy and heart failure. ATTR-CM is a type of cardiac amyloidosis caused due to misfolded and destabilized transthyretin amyloid protein deposits in the myocardium. Tafamidis is a transthyretin (TTR) modifying targeted drug that stabilizes and prevents tetramer dissociation and amyloid deposits. Our aim is to conduct a review of literature to determine the effect of tafamidis on the structural progression of transthyretin cardiomyopathy while also looking into all-cause mortality outcomes. Methods: A systematic search was performed in PubMed, Embase, and Cochrane using the MESH terms "Tafamidis" and “Transthyretin Amyloid cardiomyopathy.” Two authors independently reviewed article titles and abstracts. Disagreements were resolved by consensus and then adjudicated by a third author. All articles published in English up to the year 2019 were eligible for inclusion. Data was tabulated and analyzed. Studies measuring mortality outcomes and echocardiogram findings with the use tafamidis in ATTR-CM were included. Studies that did not measure mortality outcomes were excluded as well as case reports and animal studies. Results: Out of the studies identified through databases (n = 57), only 6 studies met the inclusion criteria as earlier studies delved strictly into the tolerability and safety of the drug. The studies that were included in this analysis are heterogeneous, because ATTR-CM is phenotypically heterogeneous (wild type-ATTR-CM or mutant ATTR-CM) and has varying degrees of amyloid deposits and cardiac symptoms. The role of tafamidis in reducing the effect of cardiomyopathy in transthyretin amyloid cardiomyopathy is unclear. Effects on the structural changes of the myocardium including the ejection fraction remain inconsistent. A recent multicenter, international, phase 3 randomized controlled trial shows reduction in all-cause mortality comparing tafamidis vs placebo. (29.5% vs 42.9%). Conclusions: With the recent approval of tafamidis, it is vital to review and analyze the available data to study its effects on transthyretin amyloid cardiomyopathy. While structural improvements with tafamidis therapy are inconsistent, reduction in all-cause mortality with this novel drug is promising.
Efficiency: Minimizing dose escalation steps by calculating human dosing preclinically.
Authors: Gyorffy Steve , Blunt Al , Messerschmidt Gerald L. 
Published: May 2020

e15622 Background: Historically, oncology drug development can take years to accomplish the goal of bringing new agents to patients. Scientific knowledge is evolving rapidly, transforming our understanding of the diseases at a rapid pace. This necessitates expedited drug development and approval to allow benefit for cancer patients. First-in-human administration to accelerated approval worthy data can efficiently occur in approximately two years, often in small very specific populations (individualized [precision medicine] therapy). The pre-clinical time period solidifies basic knowledge of mechanism of action, dosing, schedule, safety and efficacy both in vitroand in vivo, but adds to the development timeline of these products. Determining the correct dose has been identified by us and others as a critical issue that often leads to prolonged Phase 1 dose escalation in very expensive human testing environments.To optimize development timelines, we have targeted identification of dose (safe vs toxic and no benefit vs effective) as a critical area to define in these pre-clinical experiments. Methods: Tumor cell killing concentrations are essential to understanding the required lower limits and optimal amounts of drug available at the target cell (cancer or immune cell), with cognizant regard to toxicity in normal tissue, both a key focus of preclinical testing. Determining these concentrations in vivo are important data sources for this concept of “therapeutic index”. Defining the concentration for killing range and concentrations in total body water can then be used to calculate human starting dose that is within or near the beneficial anti-cancer concentration, but not at the predicted toxic concentration for normal human tissues. Results: By using a mathematical algorithm, we have developed a set of formula’s that can translate micro-molar or similar concentrations in vitro, and animal studies to human optimized dose escalation trials. This often involves predicting maximum tolerated dose (MTD) or optimal biologic dosing (OBD) for efficacy and safety rather than forcing the appearance of Dose Limiting Toxicities (DLT). Conclusions: This pre-clinical work has the potential to be able to decrease the in-human dose escalation time period and lead to more efficient development of novel therapeutics.
OSU-03012 induces apoptosis of gastric cancer cells through endoplasmic reticulum stress triggered inhibition of Akt and STAT3 signaling pathways.
Authors: Peng Wei , Xu Xia , Chen Xiaoxiang , Feng Jifeng , Shen Bo , Lu Jianwei 
Published: May 2020

e15630 Background: As the chemotherapeutic resistance and postoperative relapse rates of gastric cancer rise year by year, searching for novel chemoprevention compounds has become fairly imminent. 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a derivative of anti-inflammatory drug celecoxib, has recently been shown to have anti-tumor effects. But its roles and underling mechanisms in gastric cancer is rather unknown. Methods: In this study, we show for the first time that OSU-03012 inhibits the growth and potently induces the apoptosis of gastric cancer cells in vitro in a time- and dose-dependent manner. Results: We demonstrate that OSU-03012 induces cell death through endoplasmic reticulum stress (ERS) mediated up-regulation of PTEN, sequentially followed by the suppression of Akt-STAT3 axis, the activation of the mitochondrial membrane protein Bim, mitochondrial damage and finally the release of the caspase family proteases. Conclusions: Our data provide evidences to support OSU-03012 as a potential therapeutic agent for gastric cancer, which may facilitate further preclinical development of anti-tumor drugs.
Growth differentiation factor 15 (GDF-15) inhibition to increase muscle mass and function in cancer cachexia.
Authors: Peloquin Matthew , LaCarubba Brianna , Joaqium Stephanie , Weber Gregory , Stansfield John , Bezy Olivier , Kim-Muller Ja Young , Breen Danna , Wu Zhidan , Zhang Bei Betty 
Published: May 2020

e15633 Background: Almost half of cancer deaths are attributed to cancers most frequently associated with cachexia. Cachexia is a complex metabolic disease characterized by anorexia and unintentional weight loss. Skeletal muscle depletion has been recognized as a key feature of the disease, however muscle anabolic therapies have not been successful, suggesting that treatments that target multiple aspects of the disease will be most effective. Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia and weight loss and is associated with cachexia in cancer patients. In preclinical cancer cachexia models, GDF-15 inhibition is sufficient to normalize food intake and body weight, including skeletal muscle mass. However, it remains to be determined whether the increased skeletal muscle mass also results in restoration of muscle function. Therefore, we examined the effect of GDF-15 inhibition on muscle mass and function in mouse models of cancer cachexia in comparison with myostatin inhibition, an established muscle anabolic pathway. Methods: Cachectic mouse tumor models were established with subcutaneous implantation of tumor cell lines reported to be GDF-15-dependent; mouse renal cell carcinoma (RENCA) and human ovarian cancer (TOV-21G) cell lines. Mice were treated with anti-GDF-15 (mAB2) or anti-myostatin (RK35) monoclonal antibodies and skeletal muscle function was assessed in vivo via maximum force, maximum rate of contraction and half relax time. In the RENCA tumor model, GDF-15 inhibition fully restored body weight and skeletal muscle mass whereas myostatin inhibition showed only a modest effect. Results: Consistent with the muscle mass improvement, GDF-15 inhibition dramatically increased functional muscle endpoints compared to the partial effect of myostatin inhibition. Interestingly, in the TOV-21G tumor model GDF-15 inhibition only partially restored body weight, however skeletal muscle mass and muscle function were completely normalized. Consistent with the functional assessment, GDF-15 inhibition in the RENCA tumor model decreased the expression of several catabolic genes (i.e. Trim63, Fbxo32, Myh7 and Myh2). The GDF-15 effect is likely to be secondary to the reversal of anorexia since wildtype mice pair-fed to Fc-GDF-15-treated mice demonstrated equivalent muscle mass loss. Conclusions: Taken together these data suggest that GDF-15 inhibition holds potential as an effective therapeutic approach to alleviate multiple aspects of cachexia.
Studies on the efficacy of pyrotinib in the treatment of HER-2 positive advanced solid tumors.
Authors: Fan Shaoshuang , Jiang Da , Lv Yalei , Cui Yanzhi , Kong Yan , Dong Qian , Huang Fang , Zhang Xue , Wang Long , Zhou Xinliang , Jin Hui , Li Ying , Hou Ran 
Published: May 2020

e15639 Background: To explore the efficacy and safety of pyrotinib in the treatment of HER-2 positive advanced solid tumors patients. Methods: Patients with HER-2 positive advanced solid tumors in oncology department of our hospital from October 2018 to Janurary 2020 were collected. All the patients were given oral pyrotinib 400mg once a day in a 28-day cycle. The clinicopathological characteristics, treatment history, and curative effect were collected, and the adverse reactions related to the treatment were recorded. Results: 13 patients with HER-2 positive advanced solid tumors were enrolled, including 11 patients with metastatic breast cancer, 3 patients with metastatic colon cancer, 3 patients with gastric cancer. Among them, 10 patients were evaluated for efficacy and(or) side effect, of which 3 patients were excluded because they were not taken pyrotinib according to the medical order or they had no complete follow up data. The total mPFS was 5.63 months (95%CI: 2.533-5.467), partial remission (PR) were 3 cases(30%), stead diease(SD) were 6 cases(60%), progress diease was 1 case(10%). The overall response rate (ORR) and the disease control rate (DCR) were 23.1%, 69.2%, respectively. 2 patients received first-line treatment and 11 patients received second-or-further-line treatment. 11 cases of trastuzumab were changed to anti-HER-2 after treatment failure, of which 2 cases were treated with pirotinib after trastuzumab and lapatinib failed treatment. 12 cases with HER-2 overexpression and 1 case with HER-2 amplification. The incidence of pyrotinib side effects was 100%, which occurred in the first cycle of treatment and was common in grade 1 and 2. The common symptoms were diarrhea (100%), hand and foot skin reaction (38%), rash (8%), etc. Grade 3 to 4 adverse events occurred in 1 patient (8%) received pyrotinib plus capecitabine. 1 patient reduced pyrotinib dosage because of diarrhea. Nevertheless, diarrhea did not lead to discontinuation. Conclusions: The treatment of HER-2 positive advanced solid tumors with pyrotinib have good exact affect, and the toxicity could be controlled.