bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of light irradiation by light emitting diode on colon cancer cells and cancer stem cells.
Authors: Nishi Masaaki , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Takasu Chie , Eto Shohei , Teraoku Hiroki 
Published: February 2017

271 Background: Recent studies demonstrate the efficacy of irradiation from light emitting diodes (LED) for wound healing and anti-inflammation and anti-cancertherapies. However, little is known about the effects of LED in colon cancer cells. Furthermore, most solid cancers are believed to be initiated from and maintained by cancer stem cells (CSCs). The purpose of this study was to evaluate the biological response of human colon cancer cells and CSCs to LED irradiation. Methods: <Experiment 1, Effect of LED on normal cancer cells> Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were put on LED irradiation equipment with a 465 nm-, 525 nm-, or 635 nm-LED. Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. Cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively. <Experiment 2, Effect of LED on CSCs> HCT-116 cell line was cultured with fetal bovine serum in RPMI-1640 medium and its sphere was grown in serum-free non-adherent culture. Cancer sphere were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-LED. Stemness gene and cell surface markers of CSCs expressions (Oct4, CD44, Nanog, EPCAM) were analyzed by RT-PCR. Results: <Experiment 1> Viability of HT29 and HCT116 cells was lower in 465 nm-LED irradiated cultures than in control cultures, but viability of HT29 cells did not differ between control cultures and 525 nm-LED or 635 nm-LED irradiated cultures. Moreover, the expression of FAS, caspase3, capase8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue-irradiated cells. <Experiment 2> Cell viability of cancer sphere were significantly decreased by LED irradiation(p<0.05). And, stemness gene and cell surface markers of CSCs expressions (Oct4, CD44, Nanog, EPCAM) were significantly decreased by LED irradiation (p<0.05) Conclusions: LED irradiation at 465 nm inhibited the proliferation of both normal colon cancer cell lines and CSCs.
The Yale Gastrointestinal Cancer Biorepository: A comprehensive biospecimen and data resource for studying determinants of pancreatic ductal adenocarcinoma prognosis following curative-intent pancreaticoduodenectomy.
Authors: Gould Rothberg Bonnie Elyssa , Deminie Carol , Lazowski Heather , Gibson Joanna A , Cha Charles , Lacy Jill , Hochster Howard S. , Salem Ronald R 
Published: February 2017

272 Background: Although surgical resection can be curative for pancreatic ductal adenocarcinoma (PDAC), only 20% of patients qualify and, of these, only 20% survive for 5 or more years. Because tumor biology, germline genetics, environmental exposures and lifestyle factors all contribute, we designed the Yale Gastrointestinal (GI) Cancer Biorepository to partner biospecimen science best practices with comprehensive clinico-epidemiologic annotations evaluate determinants of outcome for PDAC and other GI cancers. Methods: Adult patients presenting to Yale GI Oncology Clinics with incident cancers who consent are interviewed using a validated instrument to capture demographics, medical comorbidities, family history of cancer, employment history and lifestyle choices including tobacco, alcohol, diet and physical activity. Buffy coat and 20 mL of plasma are collected pre-operatively. Surgical Pathology provides three 3 mm tissue cores to be stored in RNALater at -190°C in addition to formalin-fixed tissue blocks with time to fixation at ≤30 minutes. Confirmatory touch-preparations are required for all RNALater-preserved specimens. Periodic medical record abstraction documents recurrence, progression, treatment and vital status. Quality-of-life and lifestyle reassessments occur at 6 and 12 months post-diagnosis then annually thereafter. Results: Since our March 2012 launch, we consented 388 individuals including 57 PDAC patients undergoing pancreaticoduodenectomy with 16 (28%) having received FOLFIRINOX-based neoadjuvant therapy prior to surgery. Median follow-up is 7.9 months with 11 PDAC recurrences and 7 PDAC-related deaths confirmed. Receipt of neoadjuvant therapy trended towards downstaged cancers upon resection (p=0.08). Women (n=20) were more likely to be older (p=0.02) and trended towards less advanced cancers (p=0.06) but smoked, used aspirin similarly and have BMIs comparable with men (n=37). Exome and transcriptome analysis of tumor and germline are ongoing. Conclusions: Determinants of early-stage PDAC prognosis will emerge as this cohort matures.
Characterization of a novel mutation in fibrolamellar hepatocellular carcinoma.
Authors: Riggle Kevin M , Kenerson Heidi , Kazami Machiko , Bauer Renay , Yeung Raymond Sze , Riehle Kimberly J 
Published: February 2017

284 Background: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a subtype of HCC occurring in children and young adults in the absence of underlying liver disease. Currently, there is no effective therapy for unresectable or metastatic FL-HCC. Recent genomic analysis identified a consistent mutation in FL-HCC involving a deletion on chromosome 19 resulting in a chimeric transcript containing the 5’-region of a heat shock protein (DNAJB1) fused to the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant protein and its effects on PKA activity in human FL-HCC. Methods: We prepared tissue lysates from four snap-frozen FL-HCC samples with paired, non-tumor liver as well as adult HCCs. PKA activity was determined via a radioactive kinase assay in the presence and absence of cAMP, a PKA activator. RNA was extracted using TRIZOL, and used for qRT-PCR. Triple immuno-fluorescent labeling was performed using antibodies to PRKACA, PKA RIIα, and a nuclear marker, DRAQ5. Results: We found that expression of the chimeric transcript was increased 40-fold in FL-HCC compared to normal liver, and was significantly higher than that of wild-type DNAJB1 and PRKACA in FL-HCC. The corresponding mutant protein was highly expressed in the tumors and was unique to FL-HCC. Basal PKA activities from freshly lysed tumors and paired livers were not significantly different, but cAMP-stimulated PKA activity was significantly higher in FL-HCC tumors when compared to normal liver. Using multi-color immuno-fluorescence we detected mutant DNAJB1-PRKACA within the nucleus, while wild-type PRKACA localizes to the cytoplasm. Conclusions: The expression of DNAJB1-PRKACA is unique to FL-HCC and not found in classic forms of HCC. Markedly elevated expression of the mutant transcript is indicative of dysregulated DNAJB1 promoter activity. PKA activity in FL-HCCs remains cAMP-dependent, but is greatly enhanced in the presence of cAMP; this could reflect an altered intrinsic activity of the mutant protein and/or elevated expression. Further, the mutant protein showed aberrant localization to the nucleus. These findings suggest that DNAJB1-PRKACA in FL-HCC leads to over-activation of PKA, which may contribute to tumor development.
Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation.
Authors: Pace Emily , Adams Sharlene , Camblin Adam , Curley Michael , Rimkunas Victoria , Nie Lin , Iadevaia Sergio , Tan Gege , Baum Jason , Czibere Akos Gabor , Lugovskoy Alexey 
Published: February 2017

289 Background: Gemcitabine, the first-line treatment for pancreatic cancer, has been improved by addition of nab-paclitaxel. However, patient response to this regimen is limited. Oncogenic insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling are associated with increased cancer risk and decreased response to anti-metabolites and taxanes. Therefore, we explored MM-141, a novel bispecific antibody that blocks ErbB3 and IGF-1 receptor (IGF-1R) signaling, in combination with nab-paclitaxel and gemcitabine in preclinical models of pancreatic cancer. Methods: Combinations with MM-141, gemcitabine, and nab-paclitaxel were investigated in pancreatic cancer cell lines, in vitro and in vivo. The effects of MM-141, gemcitabine, and nab-paclitaxel on tumor growth and signaling were measured by 3D spheroid growth, ELISA, Western, and mouse xenograft experiments. Results: In vitro studies show that IGF-1 and HRG are potent activators of AKT signaling, leading to increased pancreatic tumor cell proliferation and decreased sensitivity to gemcitabine and nab-paclitaxel. MM-141 inhibits ligand-induced AKT activation, induces IGF-1R and ErbB3 degradation better than a mixture of IGF-1R and ErbB3 antibodies, and sensitizes cells to gemcitabine and nab-paclitaxel, in vitro. In vivo, MM-141 combines favorably with a nab-paclitaxel/gemcitabine regimen, leading to curative outcomes in a subset of treated mice. Conclusions: ErbB3 and IGF-1R co-inhibition is required to inhibit AKT signaling in pancreatic adenocarcinoma cell lines. These receptors are associated with chemoresistance to gemcitabine and nab-paclitaxel, which is abrogated by co-administration with MM-141. MM-141-induced degradation of oncogenic receptor complexes is likely essential to reverse chemoresistance and enhance effects of the nab-paclitaxel/gemcitabine regimen. These data, taken together with wide-spread expression of IGF-1R and ErbB3 in Stage IV pancreatic adenocarcinoma tissue, support clinical exploration of a MM-141/nab-paclitaxel/gemcitabine regimen in frontline metastatic pancreatic cancer. Preparations for a randomized Phase 2 study are underway.
HER3 as a potential prognostic biomarker in pancreatic cancer.
Authors: Wang-Gillam Andrea , Rimkunas Victoria , Abu-Yousif Adnan , Nywening Timothy M. , Gao Feng , DeNardo David G , Linehan David , Czibere Akos Gabor , Lugovskoy Alexey 
Published: February 2017

295 Background: HER 3 is revealing itself to be increasingly important in HER family signaling. Understanding the role of HER 3 in pancreatic cancer may shed light on targeted therapy development. Methods: A large human pancreatic cancer tumor tissue microarray (TMA) was established at our institution from 165 patients with pancreatic cancer who underwent surgical resection. The TMA contains two cores from each patient. Clinical information of these patients has been prospectively maintained in a clinical database. Immunohistochemistry (IHC) was performed on the TMA using a monoclonal antibody against HER 3. An independent pathologist blinded to the patient data applied the H score to grade the expression level of HER 3. The association between expression levels of HER 3 and survival were evaluated by the Kaplan-Meyer product limit method and log-rank test, while the optimal cut-off for each marker was determined using the Martingale residuals from Cox proportional hazard models. Results: Out of 165 patients, 136 patients’ tumors were identified to have adequate tumor content for IHC analysis. The group with higher HER 3 levels at the cell membrane (n=50)(H score ≥150) had a superior overall survival compared to the low HER 3 membrane expression group (n=86) (22.5 months vs. 17 months; p=0.036). Interestingly, the group with higher expression levels at both the cell membrane and in the cytosol (n=37) (H score ≥190) had a more striking survival difference compared to the lower group (n=99) (26 months vs. 15 months; p= 0.035). Conclusions: Patients with high HER 3 expression either at the cell membrane only or at both the membrane and in the cytosol have longer survival, perhaps indicating a lower heregulin and inactive HER 3 signaling. Additional biomarker analyses are ongoing. The functional role of HER 3 in pancreatic cancer is being further explored to assist clinical evaluation of HER 3 targeting in pancreatic cancer.
Clinical characteristics and outcomes for gastric cancer patients over age 80: A retrospective case-control study.
Authors: Park Hee-Jung , Ahn Ji Yong , JUNG Hwoon-Yong , Lee Jeong Hoon , Choi Kwi-Sook , Jung Kee Wook , Kim Do Hoon , Choi Kee Don , Song Ho June , Lee Gin Hyug , Kim Jin-Ho , Han Seungbong 
Published: February 2017

30 Background: The average human life expectancy is increasing worldwide, thus proportion of elderly gastric cancer patients are also increasing. In this study, we investigated the clinical and oncologic outcomes of gastric cancer in patients over 80 years old through a case-control study. Methods: From January 2004 to December 2010, 291 patients aged over 81 years old (case group) were diagnosed and treated with gastric cancer at the Asan Medical Center. During the same period, 291 patients aged 18 to 80 years old were selected as control group. The clinical findings, histopathological parameters, and clinical outcomes of gastric cancer were reviewed retrospectively and compared between the two groups. Results: There were significant differences in overall 5-year survival rate between the two groups (30.9% vs 73.8%, P< 0.001). When analysis was confined to resectable elderly patients with favorable performance of American Society of Anesthesiologists (ASA) score 1 or 2, curative resection group showed significantly better overall 3- and 5-year survival rate than the conservative treatment group (73.7% and 58.8% vs 29.8% and 0%, respectively). In multivariate analysis, lower BMI and advanced TNM stage were found to be independent prognostic predictors for poorer survival. ASA score showed borderline significance for predictors for poorer survival (P=0.087). Conclusions: Although elderly patients showed advanced stage at diagnosis and poor prognosis compared to non-elderly patients, elderly patients with good performance could benefit from curative resection of gastric cancer, thus the clinical decision whether to undergo curative resection or conservative management should be made on individualized approach.
Exceptional responses in patients with upper gastrointestinal malignancies enrolled in first-in-man studies: 2002-2012.
Authors: Reese Zachary L , Tometich Danielle , Patel Shiven B. , Sharma Sunil , Garrido-Laguna Ignacio 
Published: February 2017

311 Background: First-in-man (FIM) studies test the efficacy and safety of novel therapeutic agents with proven in vitro activity when used for the first time in humans. Patients with advanced upper gastrointestinal malignancies (UGIM) have limited systemic treatment options. We established a database of FIM studies published from 2002-2012 to identify exceptional responders in patients with UGIM. Methods: Using a Scopus search, we compiled a database of published FIM studies enrolling patients with UGIM between 2002 and 2012. We identified exceptional responders to therapy among these patients as a complete response or a partial response lasting at least 6 months. Results: We identified 84 FIM studies enrolling at least one patient with UGIM. In total 554 patients with UGIM were enrolled including 290 pancreatic adenocarcinomas (52.3%), 110 gastric adenocarcinomas (19.9%), 83 esophageal carcinomas (15.0%), 41 hepatocellular carcinomas (7.4%), and 30 cholangiocarcinomas/gallbladder carcinomas (5.4%). One patient with pancreatic cancer treated with bosutinib, a src kinase inhibitor, had a complete response with a progression-free survival (PFS) of 42 months. Four partial responses were reported including one pancreatic cancer patient treated with CHR-3996, a histone deacetylase inhibitor (PFS 12 mo); two pancreatic cancer patients treated with trametinib, a MEK inhibitor (10 and 11.75 mo); and one cholangiocarcinoma patient treated with SB-743921, a kinesin inhibitor (11 mo). Two additional partial responses were noted without available PFS data including one pancreatic cancer patient treated with KOS-1584, a second generation epothilone, and one gastric cancer patient treated with apatinib, a VEGFR-2 inhibitor. Conclusions: Exceptional responses are seen in patients with UGIM enrolled in FIM studies. Actionable genetic aberrations may be driving disease in these patients. Further studies are needed to understand these responses at the molecular level. These molecular studies could open new treatment opportunities for patients with advanced UGIM.
LDH serum levels as prognostic and predictive factor in advanced biliary tract cancer patients treated with first-line chemotherapy.
Authors: Faloppi Luca , Del Prete Michela , Scartozzi Mario , Santini Daniele , Bianconi Maristella , Giampieri Riccardo , Cascinu Stefano 
Published: February 2017

313 Background: Previous data suggested that LDH serum levels may be associated with tumour hypoxia and VEGFA and VEGFR-1 over-expression. LDH may then represent an indirect marker of activated tumour neo-angiogenesis and worse prognosis in many tumour types. In our analysis, we analyzed the role of LDH serum levels in predicting clinical outcome for biliary tract cancer patients treated with first-line cisplatin and gemcitabine chemotherapy, to individuate a potentially reliable and easy to use marker for patients stratification. Methods: 71 advanced biliary tract cancer patients treated with cisplatin and gemcitabine in first-line chemotherapy were available for our analysis. For all patients, LDH values were collected within one month before treatment beginning. We chose the laboratory cut-off (Upper Normal Rate, UNR) as LDH cut-off value (450 U/l) and then we divided the patients into two groups (A and B, below and above the UNR respectively). Survival distribution was estimated by the Kaplan-Meier method. Disease control rate (DCR) was assessed with chi-square test. A significant level of 0.05 was chosen to assess the statistical significance. Results: Patients in group A (46 patients) and B (25 patients) proved homogeneous for all clinical characteristics analyzed. Median progression free survival (PFS) was 3.97 months and 1.8 months respectively in group A (patients with LDH level below the UNR) and in group B (patients with LDH level above the UNR), p=0.0064 (HR=2.07, 95%CI: 1.07-3.99). Median overall survival (OS) was 9.24 months and 2.55 months in group A and B respectively, p<0.0001 (HR=2.93; 95%CI: 1.37-6.27). DCR was 65% in group A vs. 21% in group B (p=0.004). Conclusions: Our observations seem to suggest a prognostic role of LDH in biliary tract cancer patients. Our findings showing an improved PFS and DCR in patients with low LDH serum levels also suggest a possible predictive role in patients treated with a cisplatin and gemcitabine regimen as first-line chemotherapy. After further confirmation in larger trial, these results may be relevant for a better patients stratification and selection.
Next-generation sequencing (NGS) in advanced pancreatic adenocarcinoma (PA): A Brazilian experience.
Authors: Moreira Raphael Brandao , Alessandretti Matheus Bongers , Lino Aline Da Rocha , Martins Junior Rodnei Merlrina , Amarante Marcus Paulo Fernandes , Gomes Jessica Ribeiro , Sousa Tarcia Tarciane Soares de , Abrahao Carina Mina , Kawamura Haddad Carolina , Peixoto Renata D'Alpino , Maluf Fernando C. , Buzaid Antonio C. , Cruz Marcelo Rocha ,   COAEM
Published: February 2017

315 Background: Metastatic PA is a lethal malignancy with poor prognosis and limited therapeutic options. We hypothesized that a comprehensive next-generation sequencing (NGS) assay could identify novel therapy targets not routinely explored in PA patients. Methods: We included patients with advanced pancreatic adenocarcinoma (PA) with accessible lesion for biopsy. Paraffin-embedded tumor tissues were evaluated by the method of NGS (Foundation Medicine, Cambridge, MA, USA). Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from 10 PA specimens and sequenced to high, uniform coverage. Genomic alterations (GAs), were characterized and reported for each patient sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies either available on the market or in registered clinical trials. Results: A total of 10 PA patients were included. Median age was 56 years (range 31-79). All cases harbored at least one GA with a mean of 2.7 actionable GAs per tumor. The most common actionable GAs were KRAS (90%), PTCH1 (20%), STK11 (10%) and GNAS (10%). KRAS mutations potentially treatable with MEK-inhibitor were identified in 9 patients. However, none of them received a MEK-inhibitor. Activating STK11 point mutations not detectable by IHC/FISH, potentially targetable with m-Tor inhibitor therapies were identified in 1 patient, who received everolimus and had a long-lasting (> 6 months) partial response. Conclusions: NGS of PA was able to reveal genomic alterations that may be potentially responsive to available targeted therapy. We are just at the dawn of exploring this strategy and NGS can effectively contribute for increasing the understanding of the disease.
Aurora kinase A inhibition in combination with proapoptotic BH3-mimetic for treatment of pancreatic cancer.
Authors: Kim Edward Jae-hoon , Chinn Danielle C. , Semrad Thomas John , Mack Philip C. 
Published: February 2017

316 Background: BH3-mimetics were designed to inhibit the anti-apoptotic members of the Bcl-2 family of proteins. BH3-mimetics in clinical development do not inhibit the Bcl-2 protein Mcl1, which is often active in pancreatic cancer. However, Mcl1 level can be decreased by mitotic arrest. Therefore, drugs that cause mitotic arrest may augment apoptosis induced by BH3-mimetics. Aurora Kinase A (AKA), also commonly overexpressed in pancreatic cancer, regulates mitotic spindle assembly and centrosome maturation and its inhibition leads to M-phase arrest. We hypothesized that inhibiting AKA would increase sensitivity of pancreatic cancer cells to BH3-mimetic-induced apoptosis. Methods: Pancreatic cancer cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) were evaluated for AKA protein expression by Western blot (WB). Baseline cell cycle distribution was evaluated by flow cytometry. All four cell lines were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the Celltiter-Fluor assay. Apoptosis was evaluated by WB for cleaved PARP and caspase 3. Percentage of cells undergoing apoptosis was quantitated using flow cytometry of annexin V and propidium iodide stained cells. Results: AKA expression varied between cell lines but correlated with percentage of cells in G2/M. Level of AKA expression did not appear to correlate with response to MLN8237. However, MLN8237 did induce mitotic arrest resulting in an increase in the G2/M fraction. Cell viability assays revealed limited sensitivity to MLN8237 or ABT-263 alone. MIA PaCa-2 cells were the most sensitive to MLN8237 with IC50 ~0.09µM and HPAF-II cells were the most sensitive to ABT-263 with IC50 0.6µM. MLN8237 lowered the IC50of ABT-263 in all 4 cell lines. Chou-Talalay plots exhibited a combination index < 1 in each cell line, confirming synergy. WB for cleaved PARP and caspase 3 showed increased apoptosis with the combination. The percentage of cells undergoing apoptosis also increased with the combination in each cell line. Conclusions: Inhibition of AKA synergistically augments BH3-mimetic-induced apoptosis in pancreatic cancer cells.