tbuckley/cabot-search huggingface dataset:
The Pan Class-I PI3K Inhibitor Copanlisib Has Preclinical Activity in Mantle Cell Lymphoma, Marginal Zone Lymphoma and Chronic Lymphocytic Leukemia As Single Agent and in Combination with Other Targeted and Conventional Agents
Authors: Eugenio Gaudio, Ivo Kwee, Filippo Spriano, Chiara Tarantelli, Andrea Rinaldi, Thibaud Jourdan, Melanie Berthold, Alberto Arribas, Anastasios Stathis, Davide Rossi, Martin Lange, Oliver Politz, Emanuele Zucca, Francesco Bertoni
Journal: Blood (2016)
Patterns of care in adjuvant systemic therapy of patients with stage III melanoma: A U.S. population-based study.
Authors: Boyu Hu, Henry B. Koon, Julian Kim
Journal: Journal of Clinical Oncology (2012)

8595 Background: Use of adjuvant systemic therapy in patients with stage III melanoma is widely known to be variable based upon multiple factors such as patient age and comorbidities as well as the preference and even geographic location of the oncologist and patient. The purpose of this study was to compare the use of adjuvant therapy among patients treated in teaching hospitals and community hospitals. Methods: The study population consisted of patients with stage III melanoma enrolled into the National Cancer Database (NCDB) between 2000-2008. Patients were selected based upon surgery as the first course of therapy which resulted in a total of 27,353 eligible for analysis. The study population was then categorized into those who were treated at Teaching Hospitals (TH) including National Cancer Institute-designated cancer centers or Community Hospitals (CH). Multiple variables including age, median household income, insurance status, race and overall survival were compared between patients in the two hospital groups. Results: The overall proportion of stage III patients who received adjuvant systemic therapy was approximately 30%. There was no difference in the proportion of patients receiving adjuvant systemic therapy between patients treated in TH as compared to CH, and there was no obvious trend towards increased use over time. Of interest was that the cohort of patients designated as being treated at TH had a higher proportion of patients less than 70 years old as compared to CH. Median household income was found to be higher in patients treated at TH. Finally, despite the observation that the proportion of patients who received adjuvant therapy was not different, there a significantly higher 5-year overall survival in patients treated at TH as compared to CH. Conclusions: Although the proportion of patients who received adjuvant systemic therapy was comparable in TH and CH, there was a significant increase in 5-year overall survival within TH. Additional factors such as age, lesser comorbidities, more favorable socioeconomic factors or other unmeasured factors such as type of adjuvant therapy or whether adjuvant therapy was completed may have contributed to the improved survival in patients treated at TH.
Emotions in attacker-defender conflicts
Authors: Patricia Cernadas Curotto, Eran Halperin, David Sander, Olga Klimecki
Journal: Behavioral and Brain Sciences (2019)

Abstract The distinction between attackers and defenders might help refine the understanding of the role of emotions in conflicts. Here, we briefly discuss differences between attackers and defenders in terms of appraisals, action tendencies, emotional preferences, and brain activities. Finally, we outline how attackers and defenders may differ in their response to emotion-based interventions that aim to promote conflict resolution.
Single nucleotide polymorphisms analysis and correlation to expression microarray data in patients with sezary syndrome
Authors: Elisabetta Caprini, Diego Arcelli, Maria Grazia Narducci, Maria Cristina Picchio, Cristina Lazzeri, Mauro Helmer-Citterich, Marina Frontani, Francesca Sampogna, Cristina Cristofoletti, Valeria Tocco, Antonella Bresin, Enrico Scala, Giannandrea Baliva, Giandomenico Russo
Journal: Cancer Research (2006)

158  Sezary Syndrome (SS) is a rare form of Cutaneous T-Cell Lymphoma (CTCL) characterised by a distinct metastatic pattern mainly involving skin and blood. Exact pathogenesis of this disease is at the moment unknown and no characteristic translocation or loss of tumor suppressor has been identified. We have observed and collected samples from 29 patients in the last 8 years and have performed microarray data either for expression and genomic single nucleotide polymorphisms analysis (SNPs). We utilized oligonucleotide microarray to interrogate the expression of 22,215 known genes using the Affymetrix Human Genome U133A Array on RNA of 14 sorted CD4 T-lymphocytes from peripheral blood lymphocytes of healthy individuals either in the resting phase (T-CD4R) or activated (T-CD4A) with a bacterial superantigen (toxic shock syndrome-toxic-1). We compared these RNAs to sorted and clonal RNA samples derived from SS patients (T-CD4S) (> 95% were tumor cells as assed by staining with Vbeta monoclonal antybody). We also allelotyped tumour and autologous normal samples for over 10,000 SNPs in a set of 13 patients. Our preliminary results show that LOH (Loss of Heterozygosity) involve the following chromosomal regions: 9p21.2p21.1(31%), 9q21.2q21.32(31%), 10p12.1p11.21 (38%), 10p11.21q11.21(31%), 10q21.1q21.3(31%), 10q23.1q25.3(46%), 17p13.3-17q11.1(62%). Gains were most frequent at chromosome 17q(54%) and chromosome 8. This latter one results entirely duplicated in 3 out of 13 patients, while smaller common amplifications encompass regions 8q12.3q13.3(46%)and 8q21.3q22.3(46%). The correlation between pattern of consistent losses in genomic areas and the expression profile has been variously investigated either functionally or at informatic level and it is being currently evaluated against clinical-pathological features.
Comparison of gene-expression profiles between liver fluke- and non-liver fluke-associated intrahepatic cholangiocarcinomas using a genome-wide cDNA microarray
Authors: Natini Jinawath, Yaovalux Chamgramol, Yoichi Furukawa, Kazutaka Obama, Banchob Sripa, Chawalit Pairojkul, Yusuke Nakamura
Journal: Cancer Research (2005)

3552  Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver and its incidence is high in Southeast Asia, especially in northeastern part of Thailand, Laos and Cambodia. The majority of ICCs in this region are associated with chronic inflammation due to infection with liver flukes, particularly Opisthorchis viverrini (OV), in combination with nitrosamines from food, whereas ICCs in Japan are mainly associated with chronic inflammation due to other factors, such as primary sclerosing cholangitis or hepatolithiasis. Prognosis of ICC is very poor as surgical resection still remains the only curative treatment and no effective anti-cancer drugs are available. To better understand the common mechanisms underlying ICCs and clarify specific molecular characteristics of OV-associated ICC, we analyzed the global gene-expression profiles of 40 laser-microbeam-microdissected ICCs corresponded to 20 OV-associated ICCs from Thai patients and 20 non OV-associated ICCs from Japanese patients using a cDNA microarray containing 27,648 genes. We identified 83 genes that were commonly upregulated and 325 genes that were downregulated compared to non-cancerous biliary epithelial cells. Unsupervised hierarchical cluster analysis successfully separated the 40 ICCs into two major branches according to the Thai and Japanese groups, indicating that the difference in etiological factors indeed conferred the distinct gene-expression profiles between the two groups. Further comparison of the expression profiles of OV-associated with those of non OV-associated ICCs using supervised hierarchical clustering identified 27 discriminating genes that may represent molecular signatures of each group. Among OV-associated ICCs, comparison between tumors with lymph-node metastasis and those without metastasis identified 27 genes associated with lymph-node involvement. These data provide profound insight into mechanisms underlying ICC and may also serve as a starting point for the identification of novel diagnostic markers and/or therapeutic targets for ICC.
Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis
Authors: Sanguk Yun, Rui Hu, Melanie E. Schwaemmle, Alexander N. Scherer, Zhenwu Zhuang, Anthony J. Koleske, David C. Pallas, Martin A. Schwartz
Journal: Journal of Clinical Investigation (2019)

Fibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-prone regions of arteries, and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55α complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.
Studies of Acute Respiratory Illnesses Caused by Respiratory Syncytial Virus
Authors: Laurella McClelland, Maurice R. Hilleman, Vincent V. Hamparian, Albert Ketler, Charles M. Reilly, David Cornfeld, Joseph Stokes
Journal: New England Journal of Medicine (1961)

FIRST recovery of the respiratory syncytial or chimpanzee-coryza agent (CCA) was reported by Morris et al.1 in 1956. These workers isolated the virus from chimpanzees in an epidemic of acute respiratory illness and from a laboratory worker who was in contact with the animals. Chanock et al.,2 , 3 in 1957, described the recovery of two strains of the virus from infants with lower-respiratory-tract infection and demonstrated increases in antibody against the agent among patients with respiratory disease and controls. Three years later Rowe and Michaels4 discussed the positive laboratory diagnostic findings for this agent in an infant with pneumonia. The first . . .
Guidelines are not perfect but provide safeguards for both patients and physicians
Authors: Peter A Andrews
Journal: BMJ (2019)

Elwenspoek and colleagues review the evidence base behind the current UK guidelines for monitoring diabetes and hypertension in primary care.1 They rightly conclude that most current guidelines are based on expert opinion and consensus rather than “hard” or published evidence. 

The authors argue that unnecessary testing in primary care can lead to false positive and false negative results, increased workload, and higher …
Analysis of Other Confounding Factors Is Mandatory before Considering That Long-Acting Erythropoiesis Stimulating Agents Are Deleterious to Patients on Dialysis
Authors: Guy Rostoker, Fanny Lepeytre, Jacques Rottembourg
Journal: Journal of the American Society of Nephrology (2019)

In their recently published article, Sakaguchi et al.1 analyzed data from the renal registry of the Japanese Society for Dialysis Therapy (comprising 194,698 patients on hemodialysis followed for a median time of 2 years) and found increased mortality (13%) in patients treated with long-acting erythropoiesis-stimulating agents, namely darbepoetin and epoetin β pegol, when compared with epoetins (α, β, and κ) with a shorter biologic t1/2. These authors performed a survival analysis using Cox proportional hazard models adjusted for various covariates known to influence survival in patients on dialysis.1 In addition to the factors included in their models, other confounding factors are also known to influence mortality in patients with ESKD on hemodialysis and should also be analyzed as covariates. These include the Charlson comorbidity index (validated in both patients on hemodialysis and peritoneal dialysis worldwide, and which includes items other than age, diabetes, and cardiovascular disease per se) and also the type of vascular access (native fistula versus catheter, although the percentage of dialysis catheters is known to be low in Japan).2 Most importantly, two other factors related to the dialysis technique itself should also be analyzed in Cox proportional hazard models as time-dependent covariates because they could strongly influence mortality and lead to spurious conclusions: First, the type of dialysis membrane: Abe et al.3 (who were involved in the study published in JASN) analyzed the same registry in Japan in 2017 and elegantly showed that polymethyl methacrylate and polyethersulfone dialysis membranes were associated with a lower probability of death after 2 years of follow-up in patients with ESKD treated by hemodialysis (polymethyl methacrylate, −16%; polyethersulfone, −12%). Second, more recently, Mercadal et al.4 of the French dialysis registry (Renal Epidemiology and Information Network) highlighted an increased risk of death as high as 40% in French patients with ESKD on hemodialysis that was associated with the use of citrate dialysates as compared with classic dialysates containing either acetate or hydrochloric acid, leading the French Drugs and Devices Agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé) to implement a national materiovigilance survey. Finally, in Sakaguchi et al.’s study,1 the lack of analysis of the influence (protective, neutral, or detrimental) of oral and parental (low-dose) iron therapy limits the validity of the conclusions. Thus, detailed analyses of all possible confounding factors are mandatory before considering that long-acting erythropoiesis-stimulating agents (darbepoetin and epoetin β pegol) are deleterious in patients with ESKD on hemodialysis. Disclosures None.
IGFBP-3 suppresses angiogenesis through inhibition of FGF-2 expression
Authors: Jai-Hyun Kim, Seung-Hyun Oh, Waun Ki Hong, Ho-Young Lee
Journal: Cancer Research (2006)

253  Background: Angiogenesis, the generation of new blood vessels, is an essential step in the transition of a tumor, malignant growth and also a multiple process including endothelial membrane degradation, cell migration, branching, and proliferation. The insulin-like growth factor (IGF) system9s possible role in stimulating angiogenesis has emerged recently with the discoveries showing induction of vascular endothelial growth factor (VEGF) by IGF-1 and the synergistic stimulation of angiogenesis by IGF-II and EGF. IGFBP-3 has shown antiproliferative effects on vascular endothelial cells. On the baasis of these findings this study was conducted to investigate action mechanism of IGFBP-3 in inhibiting angiogenesis in non-small cell lung cancer cells (NSCLC). Methods: The anti-angiogenic activities of IGFBP-3 were evaluated in vitro and in vivo by testing the effects of IGFBP3 on vascular endothelial cell proliferation, capillary tube formation, endothelial cell sprouting from chick aortic arch and vessel formation in the Matrigel. The effect of IGFBP-3 on the expression of angiogenic factors was assessed in a subset of NSCLC cell lines using luciferase assay, RT-PCR, immunohistochemistry, northern blot and western blot analyses. Results: We found that IGFBP-3 inhibited tumor growth and angiogenesis. Overexpression of IGFBP-3 suppressed the FGF-2 gene expression at the level of transcription. In addition, knock down of IGFBP-3 expression by the use of siRNA activated the FGF-2 expression in NSCLC cell lines. Conclusions: These results suggest that IGFBP-3 has anticancer activities by suppressing FGF-2 -mediated tumor angiogenesis. IGFBP-3 has a strong potential as a therapeutic agent targeting angiogenesis. Supported by the National Institutes of Health Grants R01 CA109520-01 (to H-Y. Lee) and CA100816-01A1 (to H-Y. Lee), National American Cancer Society, RSG-04-082-01-TBE 01(to H-Y. Lee).
Integrin (α6β4) dependent translational control and breast carcinoma survival.
Authors: Hongim Kim, Shile Huang, Jun Chung
Journal: Cancer Research (2007)

3040  During malignant transformation, the rich environment filled with growth factors and extra-cellular matrix is rapidly lost. In their absence, normal epithelial cells undergo anoikis, a programmed cell death. Therefore, it is highly important for carcinoma cells to maintain their survival and induce angiogenesis in tumor-micro environment. Our previous findings implicate a critical role of integrin α6β4 in the survival of breast carcinoma cells by maintaining cap-dependent translation of angiogenic/survival factor, VEGF under serum starvation via activation of the mTOR. Clearly, VEGF is only the ‘tip of the iceberg’ and, most likely, α6β4 stimulates the translation of other mRNAs that contribute to breast carcinoma survival. In addition, the mechanisms by which this integrin activates mTOR remain elusive. We have found that α6β4 activates mTOR in cooperation with its signaling partner c-Met in Akt and Ras dependent manner. Activated mTOR mediates α6β4 dependent breast carcinoma survival under stress conditions that mimic tumor micro-environment because downregulation of mTOR expression by shRNA or inhibition of mTOR acitivity via rapamycin blocks α6β4 dependent carcinoma survival. α6β4 to mTOR signaling enhances translation initiation of pro-survival and anti-apoptotic mRNAs that ultimately contribute carcinoma survival in vivo and progression. Considering that translational control is understudied, but important regulator of progression, our studies will provide the novel paradigm of integrin regulation of translation initiation that plays a pivotal role in cancer progression.
Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis
Authors: Thomas N. Burn, Lehn Weaver, Julia E. Rood, Niansheng Chu, Aaron Bodansky, Portia A. Kreiger, Edward M. Behrens
Journal: Arthritis & Rheumatology (2019)

Objective Familial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon‐γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ‐blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH. Methods IFNγ −/− Prf1 −/− mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell–intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin‐33 (IL‐33)/ST2 blockade were performed using monoclonal antibodies. Results LCMV infection of IFNγ −/− Prf1 −/− mice resulted in severe HLH‐like disease. CD8+ T cells and the IL‐33/ST2 axis remained essential mediators of disease; however, IFNγ‐independent HLH immunopathology correlated with a 10–15‐fold increase in neutrophilia ( P &lt; 0.001) and an altered cytokine milieu dominated by IL‐6, IL‐1β, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) ( P &lt; 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM‐CSF and neutrophil survival. Conclusion IFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider case‐by‐case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL‐33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ‐dependent and ‐independent manifestations of HLH/MAS.
Pharmacogenetics of peripheral neuropathy in elderly patients (&gt;65 years) with advanced gastric cancer receiving oxaliplatin-based chemotherapy within a randomized phase II study
Authors: E. Goekkurt, S. Al-Batran, L. Obermann, C. Pauligk, N. Homann, J. T. Hartmann, M. Moehler, R. D. Hofheinz, E. Gerhard, J. Stoehlmacher
Journal: Journal of Clinical Oncology (2009)

e14515 Background: Peripheral neuropathy (PNP) is a dose-limiting side effect of oxaliplatin based chemotherapy. High grade PNP may compromise quality of life especially in elderly patients (pts). A randomized multicenter phase II study was conducted to compare fluorouracil, leucovorin, oxaliplatin with or without docetaxel (FLO vs. FLOT, respectively) in elderly pts with advanced gastric cancer (AGC). Our purpose was to identify pharmacogenetic markers as predictors of high grade PNP within this study. Methods: 143 pts were enrolled in this study. Pts. were numerically &gt;65 years or numerically &gt;59 years but classified biologically &gt;65 years as defined by an Instrumental Activities of Daily Living score of &lt;8. PNP was classified according to an oxaliplatin specific scale. Genotyping was performed using PCR-based RFLP or TaqMan®-based allelic discrimination. 20 polymorphisms in 13 genes being part of the metabolism of the applied drugs or DNA repair were analyzed. Statistical analyses were based on stepwise multivariate cox regression models and included genotypes and clinical parameters. Results: Median age was 71 years (range 60–83). Pts received in median 6 cycles of treatment (range 1–12). 130 pts were evaluable for PN at time of analyses. Of these, 68 received FLO and 62 received FLOT. Cumulative grade 3 PNP occurred in 49% of pts without a significant difference between FLO and FLOT receiving pts (44% and 53%, respectively, p=0.4). Genotypes of TS and MTHFR could be identified as independent risk factors for grade 3 PNP by multivariate analyses. Pts carrying a TS promoter genotype known to be associated with low TS expression (2R/2R, 2R/3RC, 3RC/3RC) were at higher risk for developing grade 3 PNP compared to pts without one of these genotypes (OR 3.0 [95%CI 1.27; 7.06], p=0.01). Pts carrying MTHFR1298AC or CC genotypes were also at higher risk for experiencing grade 3 PNP compared to pts with the wildtype MTHFR-1298AA genotype (OR 3.1 [95%CI 1.26; 7.60], p=0.01). In fact, 89% of pts that experienced grade 3 PNP were carriers of at least one of these risk genotypes. Conclusions: Polymorphisms of TS and MTHFR might be associated with grade 3 PNP in AGC pts receiving oxaliplatin based chemotherapy. No significant financial relationships to disclose.