tbuckley/cabot-search huggingface dataset:
Abstract #2781: XIAP inhibitors prime childhood acute leukemia cells for TRAIL-induced apoptosis, overcome Bcl-2-mediated resistance and exert anti-leukemic activity in a NOD/SCID mouse model of childhood acute leukemia
Authors: Melanie Fakler, Sandra Loeder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus-Michael Debatin, Simone Fulda
Journal: Cancer Research (2009)

Children with high risk acute lymphoblastic leukemia (ALL) do not respond well to current treatments. This failure is, at least in part, due to defects in apoptosis programs. Therefore, new strategies are required that counter apoptosis resistance in order to improve the poor prognosis of high risk pediatric acute leukemia. Since XIAP, a member of \#8220;Inhibitor of Apoptosis\#8221; (IAP) proteins, is expressed at high levels in acute leukemia and blocks apoptosis at a central point of the apoptotic machinery, XIAP may present a suitable molecular target for therapeutic intervention. Here, we report that neutralizing XIAP by small molecule inhibitors is a novel and effective approach to sensitize childhood acute leukemia cells for TRAIL- or chemotherapy-induced apoptosis. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to induce apoptosis in acute lymphoblastic leukemia cells. Also, XIAP inhibitors act in concert with TRAIL to reduce clonogenic growth of ALL cells demonstrating that they suppress longterm survival. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Intriguingly, XIAP inhibitors overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Thus, XIAP inhibitors combined with TRAIL even break Bcl-2-imposed resistance, a defect in the apoptotic pathway that is common in acute leukemia and associated with poor prognosis. Further, XIAP inhibitors prime ALL cells for apoptosis induced by various anti-leukemic drugs, e.g. cytarabine, doxorubicin, etoposide and 6-mercaptopurine, or by agonistic anti-CD95 antibody. Notably, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In contrast to malignant cells, XIAP inhibitors at equimolar concentrations alone or in combination with TRAIL are non-toxic to normal peripheral blood lymphocytes despite expression of the apoptosis-inducing TRAIL receptors on the cell surface, pointing to a therapeutic window. Most importantly, XIAP inhibitors significantly reduce leukemic burden in vivo in a mouse model of pediatric ALL engrafted in NOD/SCID mice. Thus, small molecule XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood acute leukemia.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2781.
Indwelling long-line method for suturing lower eyelid incisions
Authors: Xingfan Mo, Jingjing Li, Fanghua He, Minzhi Wu, Liang Zhao
Journal: Journal of the American Academy of Dermatology (2019)

After resecting skin masses, incisions are sutured for wound closure. Preventing damage and not compromising the function of the surrounding tissue during suturing is critical. After resecting skin lesions and suturing wounds on the lower eyelid, the end of the suture (usually ∼0.5 cm in length)1 can cause contact injury to the upper eyelid or the cornea during blinking. A drastic reduction of the indwelling suture length in attempt to avoid this injury can complicate suture removal.
Antenatal Therapy for Fetal Supraventricular Tachyarrhythmias
Authors: Takekazu Miyoshi, Yasuki Maeno, Toshimitsu Hamasaki, Noboru Inamura, Satoshi Yasukochi, Motoyoshi Kawataki, Hitoshi Horigome, Hitoshi Yoda, Mio Taketazu, Masaki Nii, Akiko Hagiwara, Hitoshi Kato, Wataru Shimizu, Isao Shiraishi, Heima Sakaguchi, Keiko Ueda, Shinji Katsuragi, Haruko Yamamoto, Haruhiko Sago, Tomoaki Ikeda
Journal: Journal of the American College of Cardiology (2019)
Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis
Authors: Kimon Stamatelopoulos, Georgios Georgiopoulos, Fani Athanasouli, Panagiota-Efstathia Nikolaou, Marita Lykka, Maria Roussou, Maria Gavriatopoulou, Aggeliki Laina, Georgia Trakada, Marietta Charakida, Dimitris Delialis, Ioannis Petropoulos, Constantinos Pamboukas, Efstathios Manios, Marina Karakitsou, Christos Papamichael, Aikaterini Gatsiou, Irene Lambrinoudaki, Evangelos Terpos, Konstantinos Stellos, Ioanna Andreadou, Meletios A. Dimopoulos, Efstathios Kastritis
Journal: Circulation Research (2019)

Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.
Diagnostic Yield of One-Time Colonoscopy vs One-Time Flexible Sigmoidoscopy vs Multiple Rounds of Mailed Fecal Immunohistochemical Tests in Colorectal Cancer Screening
Authors: Esmée J. Grobbee, Manon van der Vlugt, Anneke J. van Vuuren, An K. Stroobants, Rosalie C. Mallant-Hent, Iris Lansdorp-Vogelaar, Patrick M.M. Bossuyt, Ernst J. Kuipers, Evelien Dekker, Manon C.W. Spaander
Journal: Clinical Gastroenterology and Hepatology (2019)
The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy
Authors: Todd C. Knepper, Meagan Montesion, Jeffery S. Russell, Ethan S. Sokol, Garrett M. Frampton, Vincent A. Miller, Lee A. Albacker, Howard L. McLeod, Zeynep Eroglu, Nikhil I. Khushalani, Vernon K. Sondak, Jane L. Messina, Michael J. Schell, James A. DeCaprio, Kenneth Y. Tsai, Andrew S. Brohl
Journal: Clinical Cancer Research (2019)

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond (P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively).We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.
TAp63γ regulates hOgg1
Authors: Sunil Upadhyay, Aditi Chatterjee, Barry Trink, David Sidransky
Journal: Cancer Research (2007)

1076  Recently, it has been shown that p53 plays a role in BER via regulation of hOGG1. Therefore, we hypothesized that p63 might also regulate hOGG1. Ectopic expression of p63 increased OGG1 expression, while it’s knockdown by RNAi resulted in reduced OGG1 expression at both RNA and protein level. Increase in OGG1 expression by p63 was associated with decreased sensitivity to oxidative damage, while decrease in OGG1 expression by RNAi increased the sensitivity to oxidative damage. The OGG1 promoter region between -945 and -726 was found to contain p63 regulatory element. We also found that p63 bound directly to the OGG1 promoter. Our findings indicate that p63 may directly or indirectly regulate OGG1.
Low-dose interleukin-2 (IL-2) in combination with interferon-alpha (IFN) and 5-fluorouracil (5-FU) for metastatic renal cell carcinoma: final report of randomized prospective study
Authors: Ilya Tsimafeyeu, Galina Kharkevich, Lev Demidov
Journal: Cancer Research (2007)

1871  Background:  High and intermediate IL-2 regimens are difficult to recommend because of great toxicity. We reported that combination of very low-dose cytokines is effective in metastatic renal cell carcinoma (MRCC) patients (pts) by response rate with an acceptable safety profile (J. Europ Urol, Supp. 2006;5 (2):286). The secondary end-points were median overall survival (OS) and time to progression (TTP) in groups.  Methods: Eligibility criteria included histopathologically confirmed MRCC, ECOG PS 0-2, no autoimmune diseases, no brain metastases, and normal organ function. All pts are randomized to IL-2 alone, 1 MIU, iv, t.i.w., weeks 1-3 or IL-2, 1 MIU, iv, t.i.w., weeks 1-3 plus IFN 5 MIU, sc, t.i.w, weeks 1-3 or biochemotherapy group 5-FU, 500 mg/m2, iv, once a week, weeks 1-3 plus IL-2 and IFN. Cycles were repeated every three weeks. Response evaluation was performed according to RECIST every 2 cycles.  Results: From Jan 2003 to Jun 2006, 66 pts with any type of MRCC histology were randomized. Median age of the pts was 55.4 years (range 16-74). 43.9% of the patients had been previously treated by chemo- or immunotherapy. 54.5 percent of the pts had poor prognosis by MSKCC criteria. Bone metastases were present in 52.4% pts. Baseline characteristics were well balanced in groups. Pts treated with IL-2+IFN or 5-FU+IL-2+IFN had a statistically longer survival than those treated with IL-2 alone (Table). OS and TTP of pts treated with IL-2+IFN and 5-FU+IL-2+IFN were not statistically different. There were no toxicity grade 3 and 4.  The recruitment of pts in IL-2 group was terminated early (n=16) due to lack of responses.  Conclusions: Low-dose IL-2 aloneis not effective. 5-FU does not improve efficacy of the cytokine combination. Low dose IL-2 and IFN demonstrate reasonable efficacy and could be recommend for MRCC pts outside clinical trials and available target therapy. All regiments are well tolerated.
Analysis of the medical response to November 2015 Paris terrorist attacks: resource utilization according to the cause of injury
Authors: Mathieu Raux, Pierre Carli, Frédéric Lapostolle, Matthieu Langlois, Youri Yordanov, Anne-Laure Féral-Pierssens, Alexandre Woloch, Carl Ogereau, Etienne Gayat, Arié Attias, Dominique Pateron, Yves Castier, Anne François, Bertrand Ludes, Emmanuelle Dolla, Jean-Pierre Tourtier, Bruno Riou
Journal: Intensive Care Medicine (2019)
The value of pharmacogenomic analysis of microsatellite instability (MSI) and XPD, XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma
Authors: M. Artac, S. Pehlivan, S. Akcan, M. Pehlivan, T. Gelen, G. Itirli, N. H. Aksoy, M. Ozdogan, B. Savas, H. S. Bozcuk
Journal: Journal of Clinical Oncology (2006)

13011 Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort. No significant financial relationships to disclose.
Identification of metastasis-related genes by DNA microarray analyses on samples generated from a metastatic mouse model of head and neck cancer.
Authors: Zhuo G. Chen, Haiyan Wu, Xin Zhang, Mi Sun Choe, Ali A. Pirani, Kim M. Gernert, Dong M. Shin
Journal: Cancer Research (2005)

204  To identify genes that mediate metastasis of squamous cell carcinoma of head and neck (SCCHN), a novel SCCHN xenograft mouse model has been established (Zhang et al. Cancer 95:1663, 2002). Using this model we performed in vivo selection from a SCCHN cell line. In the fourth round of in vivo selection, significant incidences of metastases in lymph nodes (7/10) and lungs (6/10) were achieved from a derived SCCHN cell line as compared with its parental cell line (1/5 in lymph nodes and 0/5 in lungs). Highly metastatic SCCHN cell lines were then established from lymph node metastatic tumors. The RNA from 18 metastatic cell lines (M) and 6 parental cell lines (P) isolated from nonmetastatic xenograft tumors were subjected to DNA microarray analysis using an Affymetrix gene chip HG-U133A. GCRMA in Bioconductor (www.bioconductor.org) was used for probe analysis of the microarray data. Statistical analysis (one-way ANOVA), false discovery rate calculation (q-value   1.5) were sequentially performed to select the most significant genes. A total of 5234 genes were identified from 22,123 genes on the HG-U133A gene chip. Ontological classification and k-mean clustering of these genes revealed specific features of the metastatic SCCHN cells that are different from the non-metastatic parental cells, including (1) loss of expression of cell-cell adhesion proteins, such as down-regulation of cellular adhesion molecule E-cadherin [mean signal values (log-base 2): 2.3 (M) vs. 10.4 (P)]; (2) down-regulation of cellular feature proteins, such as a putative tumor suppressor caveolin-1 [2.6 (M) vs. 12 (P)] and a differentiation marker involucrin [2.3 (M) vs. 5.2 (P)], and up-regulation of prostate stem cell antigen [8.9 (M) vs. 3.5 (P)]; (3) up-regulation of signal transducers that induce migration and invasion, such as chemokine (C-X-C) motif receptor 4 [CXCR4, 9.0 (M) vs. 2.1 (P)]; (4) switching expression pattern of small Ca2+ binding proteins, such as enhancement of S100A4 [13.6 (M) vs. 6.3 (P)], but reduction of S100A2 [5.4 (M) vs. 13.9 (P)]; and (5) alterations of expression pattern of several cytokeratins. These genotypic changes support a phenotypic alteration, epithelia-mesenchymal transition, observed between the parental cells and their metastatic derivatives. After experimental validation, these genes as a group can potentially be used as “predictors” for lymph node metastases of SCCHN (Supported by NIH grant R21 DE014767).
Abstract #4749: Involvement of microRNA silencing in the formation of field defect for gastric carcinogenesis
Authors: Takayuki Ando, Takeichi Yoshida, Shotaro Enomoto, Kiyoshi Asada, Masae Tatematsu, Masao Ichinose, Toshiro Sugiyama, Toshikazu Ushijima
Journal: Cancer Research (2009)

Multiple occurrences of cancers are well-known for stomach, bladder, liver, colon, and esophageal cancers, and a high incidence of secondary cancers indicates that normal-appearing tissues are already predisposed to developing cancers, forming a field defect. We have previously demonstrated that aberrant DNA methylation of specific protein-coding genes is induced in normal-appearing gastric mucosae by Helicobacter Pylori (H. pylori) infection, and that accumulation of aberrant DNA methylation is deeply involved in predisposition to gastric cancers (epigenetic field defect). In this study, we aimed to clarify association of H. pylori infection and DNA methylation of microRNA (miRNA) genes, and the involvement of miRNA silencing in the field defect. First, we selected three miRNA genes (miR-124a-1, miR-124a-2, and miR-124a-3) as  in gastric cancers after analysis of six reported methylation-silenced tumor-suppressor miRNA genes (miR-124a-1, miR124a-2, miR124a-3, miR-127, miR193a, and miR-137). Methylation levels of the three genes were quantified by real-time methylation-specific PCR in 56 normal gastric mucosae of healthy volunteers (28 volunteers with H. pylori and 28 without), 45 non-cancerous gastric mucosae of gastric cancer patients (29 patients with H. pylori and 16 without), and 28 gastric cancer tissues (13 intestinal and 15 diffuse types). Among the healthy volunteers, individuals with H. pylori had 7.8-13.1-fold higher methylation levels than those without (P   Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4749.
Impact of In Vivo Protein Folding Probability on Local Fitness Landscapes
Authors: Matthew S Faber, Emily E Wrenbeck, Laura R Azouz, Paul J Steiner, Timothy A Whitehead
Journal: Molecular Biology and Evolution (2019)

It is incompletely understood how biophysical properties like protein stability impact molecular evolution and epistasis. Epistasis is defined as specific when a mutation exclusively influences the phenotypic effect of another mutation, often at physically interacting residues. In contrast, nonspecific epistasis results when a mutation is influenced by a large number of nonlocal mutations. As most mutations are pleiotropic, the in vivo folding probability-governed by basal protein stability-is thought to determine activity-enhancing mutational tolerance, implying that nonspecific epistasis is dominant. However, evidence exists for both specific and nonspecific epistasis as the prevalent factor, with limited comprehensive data sets to support either claim. Here, we use deep mutational scanning to probe how in vivo enzyme folding probability impacts local fitness landscapes. We computationally designed two different variants of the amidase AmiE with statistically indistinguishable catalytic efficiencies but lower probabilities of folding in vivo compared with wild-type. Local fitness landscapes show slight alterations among variants, with essentially the same global distribution of fitness effects. However, specific epistasis was predominant for the subset of mutations exhibiting positive sign epistasis. These mutations mapped to spatially distinct locations on AmiE near the initial mutation or proximal to the active site. Intriguingly, the majority of specific epistatic mutations were codon dependent, with different synonymous codons resulting in fitness sign reversals. Together, these results offer a nuanced view of how protein folding probability impacts local fitness landscapes and suggest that transcriptional-translational effects are as important as stability in determining evolutionary outcomes.