tbuckley/cabot-search huggingface dataset:
Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
Authors: Katia Beider, Elena Ribakovsky, Michal Abraham, Hanna Wald, Lola Weiss, Evgenia Rosenberg, Eithan Galun, Abraham Avigdor, Orly Eizenberg, Amnon Peled, Arnon Nagler
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high-affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo. Experimental Design: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bone marrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement. Results: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction. Conclusions: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL. Clin Cancer Res; 19(13); 3495–507. ©2013 AACR.
Rottlerin-induced autophagy leads to the apoptosis in breast cancer stem cells: molecular mechanisms
Authors: Dhruv Kumar, Sharmila Shankar, Rakesh K Srivastava
Journal: Molecular Cancer (2013)

Abstract Background Autophagy is an indispensable lysosomal self-digestion process involved in the degradation of aggregated proteins and damaged organelles. Autophagy is associated with the several pathological processes, including cancer. Cancer stem cells (CSCs) play significant roles in cancer initiation, progression and drug resistance. Recent studies have demonstrated the antitumor activities of plant-derived chemopreventive agent rottlerin (Rott). However, the molecular mechanism by which Rott induces autophagy in breast CSCs has not been investigated. Results The objectives of this study were to examine the molecular mechanism by which Rott induces autophagy which leads to apoptosis in breast CSCs. Treatment of breast CSCs with Rott for 24 h resulted in a concentration dependent induction of autophagy, followed by apoptosis as measured by flow cytometry. Electron microscopy confirmed the presence of autophagosomes in Rott treated breast CSCs. Western blot analysis showed that Rott treatment increased the expression of LC3, Beclin-1 and Atg12 that are accumulated during autophagy. Prolonged exposure of breast CSCs to Rott caused apoptosis which was associated with the suppression of phosphorylated Akt and mTOR, upregulation of phosphorylated AMPK, and downregulation of anti-apoptosis Bcl-2, Bcl-X L , XIAP and cIAP-1. Knock-down of Atg7 or Beclin-1 by shRNA inhibited Rott-induced autophagy at 24 h. Our study also demonstrates that pre-treatment of breast CSCs with autophagosome inhibitors 3-methyladenine and Bafilomycin, as well as protein synthesis inhibitor cycloheximide inhibited Rott-induced autophagy and apoptosis. Rott induces autophagy via extensive cytoplasmic vacuolization in breast CSCs. Molecular docking results between C2-domain of protein kinase C-delta and Rott indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for ligand binding with minimum binding affinity of ≈ 7.5 Kcal/mol. Although, autophagy inhibitors suppress the formation of cytoplasmic vacuolization and autophagy in breast CSCs, the potency of Rott to induce autophagy and apoptosis might be based on its capability to activate several pathways such as AMPK and proteasome inhibition. Conclusions A better understanding of the relationship between autophagy and apoptosis would eventually allow us to discover novel drugs for the treatment of breast cancer by eliminating CSCs.
Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans
Authors: Miklos Z. Molnar, Hazem M. Alhourani, Barry M. Wall, Jun L. Lu, Elani Streja, Kamyar Kalantar‐Zadeh, Csaba P. Kovesdy
Journal: Hepatology (2014)

An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV). The risks of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV are unclear. In a nationally representative cohort of 100,518 HCV + and 920,531 HCV – US veterans with normal baseline estimated glomerular filtration rate (eGFR), we examined the association of HCV infection with (1) all‐cause mortality, (2) incidence of decreased kidney function (defined as eGFR &lt;60 mL/min/1.73 m 2 and 25% decrease in eGFR), (3) end‐stage renal disease, and (4) rate of kidney function decline. Associations were examined in naive and adjusted Cox models (for time‐to‐event analyses) and logistic regression models (for slopes), with sequential adjustments for important confounders. Propensity‐matched cohort analysis was used in sensitivity analyses. The patients' age was 54.5 ± 13.1 (mean ± standard deviation) years, 22% were black, 92% were male, and the baseline eGFR was 88 ± 16 mL/min/1.73 m 2 . In multivariable adjusted models HCV infection was associated with a 2.2‐fold higher mortality (fully adjusted hazard ratio = 2.17, 95% confidence interval [CI] 2.13‐2.21), a 15% higher incidence of decreased kidney function (adjusted hazard ratio = 1.15, 95% CI 1.12‐1.17), a 22% higher risk of steeper slopes of eGFR (adjusted odds ratio = 1.22, 95% CI 1.19‐1.26), and a 98% higher hazard of end‐stage renal disease (adjusted hazard ratio = 1.98, 95% CI 1.81‐2.16). Quantitatively similar results were found in propensity‐matched cohort analyses. Conclusions : Infection with HCV is associated with higher mortality risk, incidence of decreased kidney function, and progressive loss of kidney function; randomized controlled trials are warranted to determine whether treatment of HCV infection can prevent the development and progression of chronic kidney disease and improve patient outcomes. (H epatology 2015;61:1495–1502)
Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease
Authors: Anna Janina Engstler, Tobias Aumiller, Christian Degen, Marion Dürr, Eva Weiss, Ina Barbara Maier, Jörn Markus Schattenberg, Cheng Jun Jin, Cathrin Sellmann, Ina Bergheim
Journal: Gut (2015)

<h3>Objective</h3> Increased fasting blood ethanol levels, suggested to stem from an increased endogenous ethanol synthesis in the GI tract, are discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to further delineate the mechanisms involved in the elevated blood ethanol levels found in patients with NAFLD. <h3>Design</h3> In 20 nutritionally and metabolically screened children displaying early signs of NAFLD and 29 controls (aged 5–8 years), ethanol plasma levels were assessed. Ethanol levels along the GI tract, in vena cava and portal vein, intestinal and faecal microbiota, and activity of alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) were measured in wild-type, ob/ob and anti-TNFα antibody (aT) treated ob/ob mice. <h3>Results</h3> Despite not differing in dietary pattern or prevalence of intestinal overgrowth, fasting ethanol levels being positively associated with measures of insulin resistance were significantly higher in children with NAFLD than in controls. Ethanol levels were similar in portal vein and chyme obtained from different parts of the GI tract between groups while ethanol levels in vena cava plasma were significantly higher in ob/ob mice. ADH activity was significantly lower in liver tissue obtained from ob/ob mice in comparison to wild-type controls and ob/ob mice treated with aT. <h3>Conclusions</h3> Taken together, our data of animal experiments suggest that increased blood ethanol levels in patients with NAFLD may result from insulin-dependent impairments of ADH activity in liver tissue rather than from an increased endogenous ethanol synthesis. <h3>Trial registration number</h3> NCT01306396.
Acute kidney injury in decompensated cirrhosis
Authors: Cynthia D Tsien, Rania Rabie, Florence Wong
Journal: Gut (2012)

Hepatorenal syndrome in cirrhosis with ascites is a well-defined entity with significant morbidity and mortality. It is unclear whether milder degrees of acute kidney injury (AKI), defined as a serum creatinine increase of over 26.4 μmol/l (0.3 mg/dl) or by 50% from baseline, also has a negative impact on patient outcomes.To determine the prevalence of AKI in cirrhosis with ascites and the impact of AKI on patient outcomes.Patients with cirrhosis with ascites and baseline serum creatinine less than 110 μmol/l, and no evidence of structural renal disease, prospectively underwent 4-6-weekly blood work-up for full blood count, biochemistry and liver function. Clinical assessments occurred every 4 months for the development of AKI and other complications.90 patients (mean age 55.8 ± 0.8 years) with a mean follow-up of 14.05 ± 1.07 months were enrolled. 82 episodes of AKI occurred in 49 patients, with the majority of episodes precipitated by a disturbance in systemic haemodynamics. The mean peak serum creatinine of the AKI episodes was within the laboratory's normal range. 73 episodes of AKI resolved; nine did not. There was no clear clinical predictor for the development or resolution of AKI. Despite resolution of most AKI episodes, a gradual and significant increase in serum creatinine and a gradual reduction in mean arterial pressure were observed during follow-up, associated with a significant reduction in survival compared with non-AKI patients.Minor increases in serum creatinine are clinically relevant and can adversely affect survival. Every effort should be made to avoid precipitation of AKI in cirrhosis and ascites.
Localization and Globalization in Conscious Vision
Authors: S. Zeki
Journal: Annual Review of Neuroscience (2001)

▪ Abstract The primate visual brain consists of many separate, functionally specialized processing systems, each consisting of several apparently hierarchical stages or nodes. The evidence reviewed here leads me to speculate (a) that the processing systems are autonomous with respect to one another, (b) that activity at each node reaches a perceptual end point at a different time, resulting in a perceptual asynchrony in vision, and (c) that, consequently, activity at each node generates a microconsciousness. Visual consciousness is therefore distributed in space and time, with the universal organizing principle of abstraction applied separately within each processing system. The consequence of spatially and temporally distributed microconsciousnesses is that their integration is a multistage, nonhierarchical process that may involve a neural “glue.”
A CHANGE IN RABBIT FIBROMA VIRUS SUGGESTING MUTATION
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1936)

A change in the type of lesion produced by the fibroma virus has been observed. At about its 18th serial transfer in domestic rabbits the virus lost its ability to induce fibromas when administered subcutaneously. Instead, lesions developing in either the subcutaneous tissue or in the testicle were predominantly inflammatory in character and partly composed of lymphocytes and large mononuclear cells in place of fibroblast-like cells. Andrewes, working with the same virus in England, has observed a somewhat similar change. Passage of my changed virus through cottontail rabbits results in a transient recovery of the capacity to produce fibromata, while similar passage of Andrewes' inflammatory virus is without effect.
Efficacy of Antibiotic Therapy for Acute Exacerbations of Mild to Moderate Chronic Obstructive Pulmonary Disease
Authors: Carl Llor, Ana Moragas, Silvia Hernández, Carolina Bayona, Marc Miravitlles
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Antimicrobial therapy remains a controversial issue in nonsevere exacerbations of chronic obstructive pulmonary disease (COPD).Objectives: To evaluate the efficacy of antibiotic therapy in moderate exacerbations of mild-to-moderate COPD.Methods: This study involved a multicenter, parallel, double-blind, placebo-controlled, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers of 10 pack-years or more with spirometrically confirmed mild-to-moderate COPD (FEV1 > 50% predicted and FEV1/FVC ratio < 0.7) and diagnosed with an exacerbation were enrolled in the study. The patients were randomized to receive amoxicillin/clavulanate 500/125 mg three times a day or placebo three times a day for 8 days.Measurements and Main Results: The primary outcome measure was clinical cure at end of therapy visit (EOT) at Days 9 to 11. A total of 310 subjects fulfilled all the criteria for efficacy analysis. A total of 117 patients with amoxicillin/clavulanate (74.1%) and 91 with placebo (59.9%) were considered cured at EOT (difference, 14.2%; 95% confidence interval, 3.7–24.3). The median time to the next exacerbation was significantly longer in patients receiving antibiotic compared with placebo (233 d [interquartile range, 110–365] compared with 160 d [interquartile range, 66–365]; P < 0.05). The best C-reactive protein serum cut-off for predicting clinical failure with placebo was 40 mg/L, with an area under the curve of 0.732 (95% confidence interval, 0.614–0.851).Conclusions: Treatment of ambulatory exacerbations of mild-to-moderate COPD with amoxicillin/clavulanate is more effective and significantly prolongs the time to the next exacerbation compared with placebo.Clinical trial registered with www.clinical.gov (NCT00495586).
Increased Urinary Excretions of Immunoglobulin G, Ceruloplasmin, and Transferrin Predict Development of Microalbuminuria in Patients With Type 2 Diabetes
Authors: T. Narita
Journal: Diabetes Care (2006)

Microalbuminuria is generally considered as the best available noninvasive predictor of diabetic nephropathy. However, several studies have shown that increases in certain urinary proteins (immunoglobin G [IgG] [1–3], transferrin [Tf] [4–7], and ceruloplasmin [CRL] [3,8]) were found in normoalbuminuric diabetic patients. Recently, we reported that in normoalbuminuric diabetic patients, there was a strong linear correlation among these urinary proteins (9). To assess whether increased urinary excretions of IgG, CRL, and Tf can predict development of microalbuminuria, we conducted a 5-year follow-up study of type 2 diabetic patients with normoalbuminuria at baseline.

In 1998 and 1999, we recruited 140 type 2 diabetic patients with normoalbuminuria from outpatients. Normoalbuminuria was defined as a urinary albumin-to-creatinine ratio <30 mg/gCr in all of three serial spot urine samples. No subjects had a history of disease other than diabetes, hypertension, or dyslipidemia.

Since urinary IgG, CRL, and Tf can be easily affected by meal protein (10,11), timed overnight urine samples were collected on three different days within 2 or 3 months for analyses of these urinary proteins and N -acetylglucosaminidase (NAG) (3,8–13). Geometric means of the results expressed as protein-to-creatinine (Cr) ratios including albumin (U-Alb/Cr, U-IgG/Cr, U-CRL/Cr, U-Tf/Cr, and U-NAG/Cr, respectively) were calculated. Increases in these parameters …
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4
Authors: John A Sayer, Edgar A Otto, John F O'Toole, Gudrun Nurnberg, Michael A Kennedy, Christian Becker, Hans Christian Hennies, Juliana Helou, Massimo Attanasio, Blake V Fausett, Boris Utsch, Hemant Khanna, Yan Liu, Iain Drummond, Isao Kawakami, Takehiro Kusakabe, Motoyuki Tsuda, Li Ma, Hwankyu Lee, Ronald G Larson, Susan J Allen, Christopher J Wilkinson, Erich A Nigg, Chengchao Shou, Concepcion Lillo, David S Williams, Bernd Hoppe, Markus J Kemper, Thomas Neuhaus, Melissa A Parisi, Ian A Glass, Marianne Petry, Andreas Kispert, Joachim Gloy, Athina Ganner, Gerd Walz, Xueliang Zhu, Daniel Goldman, Peter Nurnberg, Anand Swaroop, Michel R Leroux, Friedhelm Hildebrandt
Journal: Nature Genetics (2006)
Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles
Authors: F. Tanaka, K. Yamamoto, S. Suzuki, H. Inoue, M. Tsurumaru, Y. Kajiyama, H. Kato, H. Igaki, K. Furuta, H. Fujita, T. Tanaka, Y. Tanaka, Y. Kawashima, S. Natsugoe, T. Setoyama, S. Tokudome, K. Mimori, N. Haraguchi, H. Ishii, M. Mori
Journal: Gut (2010)

<h3>Background</h3> Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis. <h3>Objective</h3> To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors. <h3>Methods</h3> A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed. <h3>Results</h3> Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (<i>ADH1B</i>) and rs671 (<i>ALDH2</i>) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10<sup>−40</sup> and OR=4.13, p=8.4×10<sup>−76</sup>, respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk. <h3>Conclusions</h3> Analysis of <i>ADH1B</i> and <i>ALDH2</i> variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the <i>ADH1B</i> and/or <i>ALDH2</i> risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC.
Add-on effect of a smoke-quitting program in alcohol-addicted patients
Authors: Piero Ceriana, Antonella Balestrino, Ines Giorgi, Stefania Anastasi, Giovanni Vittadini, Ilaria Vietti, Cristina Pallavicini, Alberto Malovini
Journal: European Respiratory Journal (2013)

Introduction- Patients suffering from alcohol addiction often are smokers too, but their rehab programs are generally targeted to treat only drinking habits. We wanted to see whether, adding a smoke-quitting program to the usual alcohol rehab program to patients suffering from alcohol and nicotine dependency, could in some way influence the final outcome. Methods - during a 12-month period, all patients admitted to a residential alcohol-rehab program received an additional 4-hours educational smoke quitting program held by a pulmonologist, a behavioral therapist, a dietician and a psychologist. One year later all patients underwent a telephone interview in order to verify how their habits toward alcohol and smoke were changed. Fisher exact test was used for statistical analysis. Results – 67 patients with double dependency underwent alcohol and smoke rehab programs and completed follow-up; after 12 months 61% still abstained from alcohol, and, comparing patients who abstained with those who did not, we found that abstinence from alcohol increased the probability to change smoking habits (69% versus 42%, p
Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction
Authors: Josef S Smolen, José C Martinez Avila, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2011)

Background Treatment with tumour necrosis factor inhibitors (TNF-i) plus methotrexate (MTX), but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. Such disassociation of disease activity and structural damage has not been shown for biological agents other than TNF-i. Objectives To evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity. Methods A random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHEtrial on active rheumatoid arthritis (RA) despite MTX was used, which compared addition of placebo (n=117) with addition of TCZ (n=414) every 4 weeks. Baseline and 1-year values of clinical and serological variables were correlated with changes to 1 year of the total Genant-modified Sharp score (TGSS) using a Spearman test, and the progression of TGSS, erosion and joint space narrowing (JSN) scores in groups with low and high disease activity were compared for placebo and TCZ (Kruskal–Wallis). Results Baseline variables were similar among the groups. Change of TGSS was lower in patients receiving TCZ than placebo (TCZ: 0.29±0.96; placebo: 0.90±1.92; p=0.0007). In patients receiving placebo, the correlation with TGSS change was significant for baseline scores of the simplified disease activity index (SDAI; r=0.18, p=0.047) and swollen joint count 28 (r=0.22, p=0.019), with similar trends for C-reactive protein. Similar correlations were seen for SDAI, clinical disease activity index, disease activity score 28 at 1 year with x-ray change during that year (r=0.26–0.28, p=0.002–0.006). In contrast, none of the baseline or 1-year variables showed significant correlation with x-ray changes in patients receiving TCZ+MTX, suggesting a disassociation of the link between disease activity and damage by TCZ. Finally, for patients in remission or with low disease activity, progression of TGSS, erosion and JSN was similar among treatment groups (TGSS: placebo, 0.4±1.1; TCZ, 0.2±0.7; p=NS), while for patients with moderate or high disease activity placebo-treated patients progression was significantly greater (TGSS: 1.2±2.2 vs 0.4±1.2; p=0.0009). Conclusions IL-6 inhibition with TCZ plus MTX retards joint damage progression independently of its impact on disease activity. Similar effects have hitherto been reported only for TNF-i. This indicates that the effects of IL-6 inhibition on progression of joint damage in RA are among the most profound currently attainable.