tbuckley/cabot-search huggingface dataset:
Targeting Csnk1a1 in leukemia
Authors: Kimberly Stegmaier
Journal: The Journal of Experimental Medicine (2014)

The molecular dissection of the landscape of AML has been at the leading edge of cancer discovery, but the treatment of AML has remained largely unchanged.A defining feature of AML is a differentiation defect, yet current therapy focuses almost exclusively on cytotoxic chemotherapy.In this issue, Järås et al. report that Csnk1a1 inhibition induces differentiation in AML and is selectively essential for AML survival in vivo.Because Csnk1a1 is a druggable target, this work identifies a propitious new strategy for the treatment of AML and also demonstrates the value of re-mining existing data sets.In today's era of moderate-cost screening, scientific inquiry frequently begins with the generation of new screening data.A time-saving and highly cost-effective approach, however, is to re-mine already existing data sets.In a previous 2013 study, Miller et al. performed a pooled in vivo shRNA screen in primary MLL-AF9-rearranged mouse AML to identify candidate therapeutic targets.In the current study, this data was re-mined and a top scoring serine threonine kinase, Csnk1a1, prioritized.The authors demonstrated that Csnk1a1 is essential for AML cell survival in vivo, but not for the survival of normal hematopoietic stem and progenitor cells, suggesting a therapeutic window for the targeting of Csnk1a1 in patients with AML.The next step was to elucidate the mechanistic role of Csnk1a1 in AML, a critical but challenging step.Using state-of-the-art functional genomics (a targeted pooled in vivo shRNA screen) and expression profiling tools, the authors found that the inhibition of Csnk1a1 reduced Rps6 phosphorylation in AML cells, induced p53 expression, and triggered a myeloid differentiation program.Importantly, Tp53-null leukemia did not respond to knockdown nor to a small molecule inhibitor of Csnk1a1, strongly supporting the mechanistic importance of the p53 expression program to the response to Csnk1a1 inhibition.These findings raise the intriguing possibility that Csnk1a1 inhibition might represent a more generalizable treatment strategy to induce the p53 program in other Tp53 wild-type cancers.These results both illuminate the power of functional genomics in therapeutic target identification and are specifically a breakthrough in the identification of novel approaches to differentiation therapy for AML.In light of the strong therapeutic window for targeting Csnk1a1 in leukemic versus normal cells, the relative ease of drugging kinases, and the promise of differentiation treatment strategies, this study supports the medicinal development of Csnk1a1 small molecule inhibitors as an exciting potential therapeutic opportunity for patients with AML.
Association Between Aryl Hydrocarbon Receptor Genotype and Survival in Soft Tissue Sarcoma
Authors: Marianne Berwick, Giuseppe Matullo, Yan Shuang Song, Simonetta Guarrera, Gemma Dominguez, Irene Orlow, Mary Walker, Paolo Vineis
Journal: Journal of Clinical Oncology (2004)

Accumulating evidence shows that germline polymorphisms may affect survival in cancer. The purpose of this study was to investigate the association between polymorphisms in a group of candidate genes and survival with soft tissue sarcoma.We measured single nucleotide polymorphisms in the metabolizing, detoxifying, and DNA repair pathways in 120 newly diagnosed patients with soft tissue sarcoma. We assessed polymorphisms in the aryl hydrocarbon receptor (AhR-Arg554Lys), null variants of the glutathione S-transferase superfamily (GSTM1 and GSTT1), x-ray repair cross-complementing 1 and 3, and Xeroderma pigmentosum, group D (XRCC1-Arg399Gln, XRCC3-Thr241Met, XPD-Lys751Gln). We followed the patients for survival for a median of 7.6 years.Cox proportional hazards models demonstrated that a polymorphism at codon 554 in exon 10 of the AhR was significantly and adversely associated with survival (hazard ratio, 2.2; 95% CI, 1.3 to 3.9; P <.01), even while accounting for major clinical characteristics such as tumor grade, tumor size, anatomic site, and patient age.Further study of the role of the AhR polymorphism is warranted.
Pathogenic Profiles and Molecular Signatures of Antinuclear Autoantibodies Rescued from NZM2410 Lupus Mice
Authors: Zhiyan Liang, Chun Xie, Cui Chen, Desi Kreska, Kelvin Hsu, Liunan Li, Xin J. Zhou, Chandra Mohan
Journal: The Journal of Experimental Medicine (2004)

Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs.
Major Diabetes Complications Have an Impact on Total Annual Medical Cost of Type 2 Diabetes
Authors: Andrea Morsanutto, Patrizia Berto, Stefania Lopatriello, Dario Voinovich, Renzo Gelisio, Lorenzo G. Mantovani
Journal: Diabetes Care (2004)

Brandle et al. (1) found that the occurrence of diabetes-related comorbidities in type 2 diabetic patients are associated with an increase in average annual medical cost.

To investigate the medical cost attributable to type 2 diabetes, we conducted a retrospective longitudinal cost-of-care study in a diabetologic center in Italy. A priori, we estimated to validly enroll 300 type 2 diabetic patients with at least 1 year of follow-up. To this aim, we randomly selected 315 type 2 diabetic patients from a base of ∼2,000 diabetic patients attending the diabetologic center of Portogruaro during the period from January 2001 to August 2002.

Cost included hospitalizations, visits, diagnostics, and pharmacological therapies and were quantified in …
Effect of completion-time windows in the analysis of health-related quality of life outcomes in cancer patients
Authors: D.E. Ediebah, C. Coens, J.T. Maringwa, C. Quinten, E. Zikos, J. Ringash, M. King, C. Gotay, H.-H. Flechtner, J. Schmucker von Koch, J. Weis, E.F. Smit, C.-H. Köhne, A. Bottomley
Journal: Annals of Oncology (2012)

BackgroundWe examined if cancer patients' health-related quality of life (HRQoL) scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 are affected by the specific time point, before or during treatment, at which the questionnaire is completed, and whether this could bias the overall treatment comparison analyses.Patients and methodsA ‘completion-time window’ variable was created on three closed EORTC randomised control trials in lung (non-small cell lung cancer, NSCLC) and colorectal cancer (CRC) to indicate when the QLQ-30 was completed relative to chemotherapy cycle dates, defined as ‘before’, ‘on’ and ‘after’. HRQoL mean scores were calculated using a linear mixed model.ResultsStatistically significant differences (P<0.05) were observed on 6 and 5 scales for ‘on’ and ‘after’ comparisons in the NSCLC and two-group CRC trial, respectively. As for the three-group CRC trial, several statistical differences were observed in the ‘before’ to ‘on’ and the ‘on’ to ‘after’ comparisons. For all three trials, including the ‘completion-time window’ variable in the model resulted in a better fit, but no substantial changes in the treatment effects were noted.ConclusionsWe showed that considering the exact timing of completion within specified windows resulted in statistical and potentially clinically significant differences, but it did not alter the conclusions of treatment comparison in these studies.
Open and shut case for Rho A? The questions of when, where and how the small GTPase mediates the permeability of endothelial junctions
Authors: Virginia H. Huxley
Journal: Cardiovascular Research (2013)

This editorial refers to ‘Localized RhoA GTPase activity regulates dynamics of endothelial monolayer integrity’ by R. Szulcek et al. , pp. 471–482, this issue. 

It is incredible that current textbooks of Medical Physiology persist in describing the vascular endothelial lining as a passive barrier of finite permeability. Similarly, when the endothelium is observed to participate in vascular function it is treated as a homogenous population of cells possessing a limited number of signalling pathways that regulate the production of substrates that interact with neighbouring cells to regulate (or dysregulate) function. Instead, the barrier segregating flowing blood from metabolizing tissue is a complex structure composed of the endothelium with its associated basement membrane and surface glycocalyx, as well as the peripheral cells including pericytes, mast cells, and fibroblasts at the capillary level and varying coverage by smooth muscle cells in the venules and arterioles, respectively.1 This heterogeneous structure responds constantly to changing physical and chemical stimuli to regulate fluid and solute movement between compartments acutely and chronically.

It is important to also recognize that the basal barrier properties, the permeability of the microvessel wall to the spectrum of solutes and fluid in vivo, support maintenance of tissue homoeostasis with appropriate solute delivery and waste removal. These properties vary by organ,2,3 vessel type,3 age,2,3 sex,4 and disease …
A Signature Predicting Poor Prognosis in Gastric and Ovarian Cancer Represents a Coordinated Macrophage and Stromal Response
Authors: Rita A. Busuttil, Joshy George, Richard W. Tothill, Kylie Ioculano, Adam Kowalczyk, Catherine Mitchell, Stephen Lade, Patrick Tan, Izhak Haviv, Alex Boussioutas
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance. Experimental Design: Microarray data of 94-tumor and 45-benign samples derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature. Results: We identified a “stromal-response” expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature. Conclusions: We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer. Clin Cancer Res; 20(10); 2761–72. ©2014 AACR.
Effect of Expanding Medicaid for Parents on Children’s Health Insurance Coverage
Authors: Jennifer E. DeVoe, Miguel Marino, Heather Angier, Jean P. O’Malley, Courtney Crawford, Christine Nelson, Carrie J. Tillotson, Steffani R. Bailey, Charles Gallia, Rachel Gold
Journal: JAMA Pediatrics (2015)

In the United States, health insurance is not universal.Observational studies show an association between uninsured parents and children.This association persisted even after expansions in child-only public health insurance.Oregon's randomized Medicaid expansion for adults, known as the Oregon Experiment, created a rare opportunity to assess causality between parent and child coverage.OBJECTIVE To estimate the effect on a child's health insurance coverage status when (1) a parent randomly gains access to health insurance and (2) a parent obtains coverage. DESIGN, SETTING, AND PARTICIPANTSOregon Experiment randomized natural experiment assessing the results of Oregon's 2008 Medicaid expansion.We used generalized estimating equation models to examine the longitudinal effect of a parent randomly selected to apply for Medicaid on their child's Medicaid or Children's Health Insurance Program (CHIP) coverage (intent-to-treat analyses).We used per-protocol analyses to understand the impact on children's coverage when a parent was randomly selected to apply for and obtained Medicaid.Participants included 14 409 children aged 2 to 18 years whose parents participated in the Oregon Experiment.EXPOSURES For intent-to-treat analyses, the date a parent was selected to apply for Medicaid was considered the date the child was exposed to the intervention.In per-protocol analyses, exposure was defined as whether a selected parent obtained Medicaid. MAIN OUTCOMES AND MEASURESChildren's Medicaid or CHIP coverage, assessed monthly and in 6-month intervals relative to their parent's selection date. RESULTSIn the immediate period after selection, children whose parents were selected to apply significantly increased from 3830 (61.4%) to 4152 (66.6%) compared with a nonsignificant change from 5049 (61.8%) to 5044 (61.7%) for children whose parents were not selected to apply.Children whose parents were randomly selected to apply for Medicaid had 18% higher odds of being covered in the first 6 months after parent's selection compared with children whose parents were not selected (adjusted odds ratio [AOR] = 1.18; 95% CI, 1.10-1.27).The effect remained significant during months 7 to 12 (AOR = 1.11; 95% CI, 1.03-1.19);months 13 to 18 showed a positive but not significant effect (AOR = 1.07; 95% CI, 0.99-1.14).Children whose parents were selected and obtained coverage had more than double the odds of having coverage compared with children whose parents were not selected and did not gain coverage (AOR = 2.37; 95% CI, 2.14-2.64). CONCLUSIONS AND RELEVANCEChildren's odds of having Medicaid or CHIP coverage increased when their parents were randomly selected to apply for Medicaid.Children whose parents were selected and subsequently obtained coverage benefited most.This study demonstrates a causal link between parents' access to Medicaid coverage and their children's coverage.
Combination Therapy with Interleukin-6 Receptor Superantagonist Sant7 and Dexamethasone Induces Antitumor Effects in a Novel SCID-hu<i>In vivo</i>Model of Human Multiple Myeloma
Authors: Pierfrancesco Tassone, Paola Neri, Renate Burger, Rocco Savino, Masood Shammas, Laurence Catley, Klaus Podar, Dharminder Chauhan, Serena Masciari, Antonella Gozzini, Pierosandro Tagliaferri, Salvatore Venuta, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Clinical Cancer Research (2005)

Abstract Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6–dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6–dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34+ progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.
Acne vulgaris: is the bacterial population size significant?
Authors: J. H. COVE, W. J. CUNLIFFE, K. T. HOLLAND
Journal: British Journal of Dermatology (1980)

The levels of Propionibacterium acnes (P. acnes) and members of the Micrococcaceae were enumerated in two separate studies. The first investigation on the foreheads of thirty-five mild and thirty-five moderate acne patients showed no significant difference in the bacterial populations of the two groups. The second investigation of twelve patients on 250 mg tetracycline twice daily for 3 months showed no significant difference compared to pre-treatment data in the bacterial population during the successful treatment period. The data indicate that greater numbers of bacteria are not associated with increasing severity of acne and that the effectivenss of oral tetracycline in treating the disease can not be explained by a reduction in the number of viable bacteria.
Patients' voices are needed in debates on euthanasia
Authors: Yvonne Y W Mak, Glyn Elwyn, Ilora G Finlay
Journal: BMJ (2003)

Medically assisted death is legal in a few countries, and discussion about legalisation is ongoing in many others. But legalisation may be premature when we still do not know why patients want euthanasia and whether better end of life care would change their views
Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers.
Authors: L A Houghton, Y F Mangnall, N W Read
Journal: Gut (1990)

The relation between gastric emptying and the intragastric distribution of 300 ml radiolabelled beef consommé with and without 60 g margarine was investigated by performing randomised, paired gammacamera studies in seven healthy male volunteers (aged 20-22 years). The low calorie bland meal emptied rapidly from both the proximal and distal stomach after a short lag period (4-6 min), during which 24-50% of the liquid passed into the distal stomach. Addition of margarine to the liquid test meal increased the lag period (median 32 min, range 7-60 min; p less than 0.01) and decreased the slope of emptying (T1/2 lag period 88 min, 49-146 min v 15 min, 10-57 min; p less than 0.01). During the lag period there was an initial filling of the distal stomach, similar to that with the bland liquid, followed by a redistribution of between 19% and 61% (median 46%) of the distal stomach contents back into the proximal stomach. At the onset of emptying, the distal stomach filled (median 30%, range 16-34%) and during this time the proximal stomach emptied twice as fast as the whole stomach (p less than 0.05). Thereafter, the distal stomach capacity remained relatively constant while both the proximal and whole stomach emptied at similar rates. This study shows that the delay in gastric emptying of a liquid that has a high fat content is due in part to a redistribution of distal stomach contents back into the proximal stomach.
Implementation of evidence-based treatment protocols to manage fever, hyperglycaemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial
Authors: Sandy Middleton, Patrick McElduff, Jeanette Ward, Jeremy M Grimshaw, Simeon Dale, Catherine D'Este, Peta Drury, Rhonda Griffiths, N Wah Cheung, Clare Quinn, Malcolm Evans, Dominique Cadilhac, Christopher Levi
Journal: The Lancet (2011)
Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status
Authors: Ione de Brito-Ashurst, Mira Varagunam, Martin J. Raftery, Muhammad M. Yaqoob
Journal: Journal of the American Society of Nephrology (2009)

Bicarbonate supplementation preserves renal function in experimental chronic kidney disease (CKD), but whether the same benefit occurs in humans is unknown. Here, we randomly assigned 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m(2)) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard care for 2 yr. The primary end points were rate of CrCl decline, the proportion of patients with rapid decline of CrCl (>3 ml/min per 1.73 m(2)/yr), and ESRD (CrCl <10 ml/min). Secondary end points were dietary protein intake, normalized protein nitrogen appearance, serum albumin, and mid-arm muscle circumference. Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88 ml/min 1.73 m(2); P < 0.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P < 0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5 versus 33%; relative risk 0.13; 95% confidence interval 0.04 to 0.40; P < 0.001). Nutritional parameters improved significantly with bicarbonate supplementation, which was well tolerated. This study demonstrates that bicarbonate supplementation slows the rate of progression of renal failure to ESRD and improves nutritional status among patients with CKD.