tbuckley/cabot-search huggingface dataset:
Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth
Authors: Michael Dewaele, Tommaso Tabaglio, Karen Willekens, Marco Bezzi, Shun Xie Teo, Diana H.P. Low, Cheryl M. Koh, Florian Rambow, Mark Fiers, Aljosja Rogiers, Enrico Radaelli, Muthafar Al-Haddawi, Soo Yong Tan, Els Hermans, Frederic Amant, Hualong Yan, Manikandan Lakshmanan, Ratnacaram Chandrahas Koumar, Soon Thye Lim, Frederick A. Derheimer, Robert M. Campbell, Zahid Bonday, Vinay Tergaonkar, Mark Shackleton, Christine Blattner, Jean-Christophe Marine, Ernesto Guccione
Journal: Journal of Clinical Investigation (2015)

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.
A Review of: “James Stacey Taylor, Stakes and Kidneys: Why Markets in Human Body Parts are Morally Imperative”
Authors: Paul M. Hughes
Journal: The American Journal of Bioethics (2006)

"A Review of: “James Stacey Taylor, Stakes and Kidneys: Why Markets in Human Body Parts are Morally Imperative”." , 6(2), pp. 93–94
Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease
Authors: Young-Hwan Hwang, John Conklin, Winnie Chan, Nicole M. Roslin, Jannel Liu, Ning He, Kairong Wang, Jamie L. Sundsbak, Christina M. Heyer, Masoom Haider, Andrew D. Paterson, Peter C. Harris, York Pei
Journal: Journal of the American Society of Nephrology (2015)

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus ( PKD1 versus PKD2 ). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height–adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in–frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in–frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.
Factors Predictive of Use and of Benefit From Continuous Glucose Monitoring in Type 1 Diabetes
Journal: Diabetes Care (2009)

OBJECTIVE To evaluate factors associated with successful use of continuous glucose monitoring (CGM) among participants with intensively treated type 1 diabetes in the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Clinical Trial. RESEARCH DESIGN AND METHODS The 232 participants randomly assigned to the CGM group (165 with baseline A1C ≥7.0% and 67 with A1C &amp;lt;7.0%) were asked to use CGM on a daily basis. The associations of baseline factors and early CGM use with CGM use ≥6 days/week in the 6th month and with change in A1C from baseline to 6 months were evaluated in regression models. RESULTS The only baseline factors found to be associated with greater CGM use in month 6 were age ≥25 years (P &amp;lt; 0.001) and more frequent self-reported prestudy blood glucose meter measurements per day (P &amp;lt; 0.001). CGM use and the percentage of CGM glucose values between 71 and 180 mg/dl during the 1st month were predictive of CGM use in month 6 (P &amp;lt; 0.001 and P = 0.002, respectively). More frequent CGM use was associated with a greater reduction in A1C from baseline to 6 months (P &amp;lt; 0.001), a finding present in all age-groups. CONCLUSIONS After 6 months, near-daily CGM use is more frequent in intensively treated adults with type 1 diabetes than in children and adolescents, although in all age-groups near-daily CGM use is associated with a similar reduction in A1C. Frequency of blood glucose meter monitoring and initial CGM use may help predict the likelihood of long-term CGM benefit in intensively treated patients with type 1 diabetes of all ages.
Gonadal dysfunction in patients treated for metastatic germ-cell tumors.
Authors: S P Leitner, G J Bosl, D Bajorunas
Journal: Journal of Clinical Oncology (1986)

The effects of chemotherapy on endocrine function were assessed in 22 previously treated patients with germ-cell tumors and compared with the endocrine function of six previously untreated patients. Baseline and stimulated serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, thyroid-stimulating hormone (TSH), prolactin, and thyroxine (T4) were obtained. Baseline LH levels were elevated in both groups of patients, whereas basal FSH levels were significantly elevated only in treated patients (P less than .001). Following gonadotropin-releasing hormone (GnRH), levels of LH (P = .051) and FSH (P = .003) were greater in treated patients than in untreated control patients. No abnormalities of thyroid function or prolactin responsiveness were observed. Patients younger than 25 years of age at the time of treatment had lower serum levels of LH and FSH following chemotherapy than patients older than 25. Evidence for partial recovery of gonadal function was present with patients treated more than 18 months before study having lower levels of LH and FSH than those patients studied less than 18 months after treatment. These data demonstrate that frequent gonadal dysfunction exists in untreated patients with germ-cell tumors and that chemotherapy induces additional injury to both Leydig cells and the germinal epithelium. Further studies with long-term follow-up are necessary to define the pattern of gonadal recovery and to assess the potential sequelae of endogenous gonadotropin hypersecretion.
CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?
Authors: T B Haddy, M A Adde, I T Magrath
Journal: Journal of Clinical Oncology (1991)

Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).
Brief intervention in emergency department does not reduce partner violence in women, US study shows:
Authors: Susan Mayor
Journal: BMJ (2015)

A brief motivational intervention delivered during a hospital emergency department visit to women who drink heavily and experience violence from their intimate partner had no significant effect on their drinking or incidence of partner violence, a US randomised trial reported in JAMA has shown.1

Heavy drinking is closely associated with intimate partner violence, both as perpetrator and recipient. Researchers at the University of Pennsylvania in Philadelphia, USA, explored whether a brief motivational intervention designed to improve motivation and empowerment, delivered during a visit to a hospital emergency department, would reduce heavy drinking and the risk of violence in women.

The study included 600 women aged 18 to 64 who exceeded safe drinking limits, experienced partner violence, and attended one …
P1097 : Distinguishing drug induced autoimmune hepatitis from idiopatic autoimmune hepatitis
Authors: A. Ortega-Alonso, A. Castiella, M. Robles-Diaz, I. Medina-Caliz, C. Stephens, J. Sanabria, A. Gonzalez-Jimenez, B. Garcia-Muñoz, M. Garcia-Cortes, E.M. Zapata, P. Otazua, S. Blanco, M. Prieto, F. Bessone, M.C. Fernandez, H. Hallal, J. Primo, J.M. Moreno-Planas, M. Arrese, R.J. Andrade, M.I. Lucena
Journal: Journal of Hepatology (2015)
Reinfusion and serial measurements of carboplatin-mobilized peripheral-blood progenitor cells in patients receiving multiple cycles of high-dose chemotherapy.
Authors: T C Shea, J R Mason, M Breslin, E Bissent, M Mullen, R Taetle
Journal: Journal of Clinical Oncology (1994)

PURPOSE To examine the ability of carboplatin to mobilize peripheral-blood progenitor cells (PBPCs) and to examine the impact of infusing these cells on myelosuppression following multiple cycles of high-dose therapy. Fluctuations in circulating progenitor cell concentration following repeated cycles of this therapy were also measured. PATIENTS AND METHODS Eight patients received a total of 20 cycles of carboplatin 1,200 mg/m2 per course, granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d, and PBPC reinfusion every 28 days. PBPC were collected following 1 week of GM-CSF and following the first and second cycles of chemotherapy. Hematologic toxicity was correlated with the number of progenitor cells reinfused per cycle. The concentration of PBPC per milliliter of blood was measured at study entry, following GM-CSF priming, and after each cycle of chemotherapy. RESULTS We observed a strong inverse correlation between the number of PBPCs (CD34 and colony-forming unit granulocyte-macrophage [CFU-GM]), but not mononuclear cells (MNCs) reinfused and the days with neutropenia less than 500/microL and platelets less than 20,000/microL. Compared with baseline levels, the circulating PBPC concentration increased up to 27-fold following the first course of chemotherapy, but decreased toward, and eventually below, baseline following the second and third cycles of carboplatin. CONCLUSION PBPC reinfusion directly correlated with a reduction in myelosuppression following high-dose carboplatin chemotherapy. While high-dose carboplatin plus GM-CSF leads to a substantially greater mobilization of PBPC than GM-CSF alone, this effect is lost after multiple treatment cycles. These results emphasize the importance of early procurement and value of PBPC reinfusion in conjunction with multiple cycles of dose-intensive chemotherapy.
Preliminary report of a clinical trial supporting the sequential use of an attenuated E39 peptide (E39') to optimize the immunologic response to the FBP (E39+GM-CSF) vaccine
Authors: Doreen Jackson, Na Qiao, Julia M Greene, Diane Hale, John Berry, Alfred Trappey, Timothy Vreeland, Guy Clifton, Nuhad Ibrahim, Annie Toms, George E Peoples, Elizabeth A Mittendorf
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Folate Binding Protein (FBP) is overexpressed in breast, endometrial, and ovarian cancers. E39 (FBP191-199, EIWTHSYKV) is an HLA-A2 restricted FBP peptide vaccine already shown to generate significant in vivo immunologic response (IR) in a Phase I/IIa trial in endometrial and
Conversion Therapy Ineffective and Inappropriate for LGBTQ Youth
Authors: Julie A. Jacob
Journal: JAMA (2015)

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MEDICAL LIBRARIES IN SMALLER CITIES.
Authors: L H Taylor
Journal: JAMA (1900)

Excellent public libraries are springing up in our thriving smaller cities of 20,000 to 50,000 and more inhabitants. These libraries are partly the result of endowment by wealthy and public-spirited persons, partly of wise appropriations by the municipality. And smaller libraries are being established quite generally in cities of less size as well as in villages. While the larger centers are rapidly acquiring good medical libraries, thanks largely to concerted action by interested persons in the medical profession, little or nothing has been done as yet toward securing library facilities of a medical character for smaller cities and the territory naturally tributary to them. There is unquestionably good room here for undertakings of this kind. There is no need for argument in favor of the value of medical libraries within the convenient reach of physicians, whether in the city or in the country. One of the reasons for the reluctance
Emergence of Antimicrobial-Resistant<i>Escherichia coli</i>of Animal Origin Spreading in Humans
Authors: David Skurnik, Olivier Clermont, Thomas Guillard, Adrien Launay, Olga Danilchanka, Stéphanie Pons, Laure Diancourt, François Lebreton, Kristina Kadlec, Damien Roux, Deming Jiang, Sara Dion, Hugues Aschard, Maurice Denamur, Colette Cywes-Bentley, Stefan Schwarz, Olivier Tenaillon, Antoine Andremont, Bertrand Picard, John Mekalanos, Sylvain Brisse, Erick Denamur
Journal: Molecular Biology and Evolution (2015)

In the context of the great concern about the impact of human activities on the environment, we studied 403 commensal Escherichia coli/Escherichia clade strains isolated from several animal and human populations that have variable contacts to one another. Multilocus sequence typing (MLST) showed a decrease of diversity 1) in strains isolated from animals that had an increasing contact with humans and 2) in all strains that had increased antimicrobial resistance. A specific B1 phylogroup clonal complex (CC87, Institut Pasteur schema nomenclature) of animal origin was identified and characterized as being responsible for the increased antimicrobial resistance prevalence observed in strains from the environments with a high human-mediated antimicrobial pressure. CC87 strains have a high capacity of acquiring and disseminating resistance genes with specific metabolic and genetic determinants as demonstrated by high-throughput sequencing and phenotyping. They are good mouse gut colonizers but are not virulent. Our data confirm the predominant role of human activities in the emergence of antimicrobial resistance in the environmental bacterial strains and unveil a particular E. coli clonal complex of animal origin capable of spreading antimicrobial resistance to other members of microbial communities.
DMSA and DMPS-Water Soluble Antidotes for Heavy Metal Poisoning
Authors: H V Aposhian
Journal: The Annual Review of Pharmacology and Toxicology (1983)

This article reviews the pharmacological properties and the uses of two important antidotes for heavy metal poisoning. Meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-l-propanesulfonic acid, Na salt (DMPS) are relatively new antidotes-new, that is, to the western world. Although DMSA was introduced originally by Friedheim et al (1) to increase uptake of antimony during schistosomiasis therapy, Liang et al (77) at Shanghai in 1957 were the first to report its effectiveness as an antidote for heavy metal poisoning. The synthesis and some of the metal binding properties of DMPS were reported in 1956 by Petrunkin from Kiev (3). Shortly thereaf­ ter, DMPS became an official drug in the Soviet Union, where it is known as Unithiol (4). Between 1956 and 1975, DMSA and DMPS were studied extensively, at both the basic science and clinical levels, in the People's Republic of China, the Soviet Union, and Japan. Some of these investigations have been cited and can be found in an earlier review (5). In the USA and western Europe, however, these two compounds received very little attention until recently. A paper by Friedheim & Corvi (6) in 1975, dealing with DMSA for the treatment of mercury poisoning, and the recent production and availability of DMPS from Heyl & Co., Berlin, stimulated investigators to rediscover and study these two metal-binding agents. DMSA and DMPS are water soluble chemical analogs of dimercaprol (British Anti-Lewisite, BAL). In contrast to BAL, they have less toxicity, greater water solubility, and lim­ ited lipid solubility, and are effective when given orally.
Bronchoscopic Lung Cryobiopsy Increases Diagnostic Confidence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis
Authors: Sara Tomassetti, Athol U. Wells, Ulrich Costabel, Alberto Cavazza, Thomas V. Colby, Giulio Rossi, Nicola Sverzellati, Angelo Carloni, Elisa Carretta, Matteo Buccioli, Paola Tantalocco, Claudia Ravaglia, Christian Gurioli, Alessandra Dubini, Sara Piciucchi, Jay H. Ryu, Venerino Poletti
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Surgical lung biopsy is often required for a confident multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Alternative, less-invasive biopsy methods, such as bronchoscopic lung cryobiopsy (BLC), are highly desirable.To address the impact of BLC on diagnostic confidence in the multidisciplinary diagnosis of IPF.In this cross-sectional study we selected 117 patients with fibrotic interstitial lung disease without a typical usual interstitial pneumonia pattern on high-resolution computed tomography. All cases underwent lung biopsies: 58 were BLC, and 59 were surgical lung biopsy (SLB). Two clinicians, two radiologists, and two pathologists sequentially reviewed clinical-radiologic findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels.We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, P = 0.0003 and from 30 to 65%, P = 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group, respectively). The overall interobserver agreement in IPF diagnosis was similar for both approaches (BLC overall kappa, 0.96; SLB overall kappa, 0.93). IPF was the most frequent diagnosis (50 and 39% in the BLC and SLB group, respectively; P = 0.23). After the addition of histopathologic information, 17% of cases in the BLC group and 19% of cases in the SLB group, mostly idiopathic nonspecific interstitial pneumonia and hypersensitivity pneumonitis, were reclassified as IPF.BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of interstitial lung disease and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared with SLB.