259 research outputs found
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Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.
While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer
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Time to treatment and survival in veterans with lung cancer eligible for curative intent therapy.
BackgroundThe Institute of Medicine emphasizes care timeliness as an important quality metric. We assessed treatment timeliness in stage I-IIIA lung cancer patients deemed eligible for curative intent therapy and analyzed the relationship between time to treatment (TTT) and timely treatment (TT) with survival.MethodsWe retrospectively reviewed consecutive cases of stage I-IIIA lung cancer deemed eligible for curative intent therapy at the VA San Diego Healthcare System between 10/2010-4/2017. We defined TTT as days from chest tumor board to treatment initiation and TT using guideline recommendations. We used multivariable (MVA) Cox proportional hazards regressions for survival analyses.ResultsIn 177 veterans, the median TTT was 35 days (29 days for chemoradiation, 36 for surgical resection, 42 for definitive radiation). TT occurred in 33% or 77% of patients when the most or least timely guideline recommendation was used, respectively. Patient characteristics associated with longer TTT included other cancer history, high simplified comorbidity score, stage I disease, and definitive radiation treatment. In MVA, TTT and TT [HR 0.53 (95% CI 0.27, 1.01) for least timely definition] were not associated with OS in stage I-IIIA patients, or disease-free survival in subgroup analyses of 122 stage I patients [HR 1.49 (0.62, 3.59) for least timely definition].ConclusionTreatment was timely in 33-77% of veterans with lung cancer deemed eligible for curative intent therapy. TTT and TT were not associated with survival. The time interval between diagnosis and treatment may offer an opportunity to deliver or improve other cancer care
Projected impact of polypill use among US adults: Medication use, cardiovascular risk reduction, and side effects
Background
Polypills, which include multiple medications for reducing cardiovascular disease (CVD) risk in a single pill, have been proposed for population-wide use. The number of US adults eligible for polypills and potential benefits are unknown.
Methods
The National Health and Nutrition Examination Survey 2003-2004 and 2007-2008 were analyzed to estimate treatment rates for medications proposed for inclusion in polypills (aspirin, statin, an angiotensin-converting enzyme [ACE] inhibitor, and a thiazide-type diuretic for those without and a β-blocker for those with a history of myocardial infarction) among US adults. The number of coronary heart disease (CHD) and stroke events potentially prevented through polypill use was projected by published meta-analyses and 3 large population-based cohort studies. Two polypill eligibility criteria were analyzed: (1) US adults ≥55 years and (2) US adults with a history of CVD.
Results
There are 67.6 million US adults ≥55 years and 15.4 million US adults with a history of CVD and, thus, eligible for polypills using the 2 outlined criteria. In 2007 to 2008, 37.3% of US adults ≥55 years and 57.0% of those with a history of CVD were taking statins. Use of other polypill medications was also low. Polypill use by US adults aged ≥55 years is projected to potentially prevent 3.2 million CHD events and 1.7 million strokes over 10 years. Among those with a history of CVD, the potential to prevent of 0.9 million CHD events and 0.5 million strokes is projected.
Conclusions
Polypills have the potential to lower CVD incidence substantially among US adults
A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis
Abstract Background Lymph node metastasis constitutes a key event in tumor progression. The molecular control of this process is poorly understood. Heparan sulfate is a linear polysaccharide consisting of unique sulfate-modified disaccharide repeats that allow the glycan to bind a variety of proteins, including chemokines. While some chemokines may drive lymphatic trafficking of tumor cells, the functional and genetic importance of heparan sulfate as a possible mediator of chemokine actions in lymphatic metastasis has not been reported. Results We applied a loss-of-function genetic approach employing lymphatic endothelial conditional mutations in heparan sulfate biosynthesis to study the effects on tumor-lymphatic trafficking and lymph node metastasis. Lymphatic endothelial deficiency in N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in sulfating nascent heparan sulfate chains, resulted in altered lymph node metastasis in tumor-bearing gene targeted mice. This occurred in mice harboring either a pan-endothelial Ndst1 mutation or an inducible lymphatic-endothelial specific mutation in Ndst1. In addition to a marked reduction in tumor metastases to the regional lymph nodes in mutant mice, specific immuno-localization of CCL21, a heparin-binding chemokine known to regulate leukocyte and possibly tumor-cell traffic, showed a marked reduction in its ability to associate with tumor cells in mutant lymph nodes. In vitro modified chemotaxis studies targeting heparan sulfate biosynthesis in lymphatic endothelial cells revealed that heparan sulfate secreted by lymphatic endothelium is required for CCL21-dependent directional migration of murine as well as human lung carcinoma cells toward the targeted lymphatic endothelium. Lymphatic heparan sulfate was also required for binding of CCL21 to its receptor CCR7 on tumor cells as well as the activation of migration signaling pathways in tumor cells exposed to lymphatic conditioned medium. Finally, lymphatic cell-surface heparan sulfate facilitated receptor-dependent binding and concentration of CCL21 on the lymphatic endothelium, thereby serving as a mechanism to generate lymphatic chemokine gradients. Conclusions This work demonstrates the genetic importance of host lymphatic heparan sulfate in mediating chemokine dependent tumor-cell traffic in the lymphatic microenvironment. The impact on chemokine dependent lymphatic metastasis may guide novel therapeutic strategies
Spanish validation of the Internet Gaming Disorder-20 (IGD-20) Test
In recent years, problematic and addictive gaming has been a phenomenon of growing concern worldwide. In light of the increasing awareness about this issue, the latest (fifth) edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included Internet Gaming Disorder (IGD) as an area in need of more empirical research. The Internet Gaming Disorder Test (IGD-20 Test) was developed as a valid and reliable tool to assess IGD. The aim of the present study was to validate the Spanish version of the IGD-20 Test, and analyze the different profiles found among a sample of 1,074 Spanish-speaking gamers. A confirmatory factor analysis showed the validity of the Spanish version of the IGD-20 Test and its six factor structure (i.e., salience, mood modification, tolerance, withdrawal, conflict and relapse). The latent profile analysis (LPA) showed five different gamer classes. The 'disordered gamers’ class comprised 2.6% of the participants. Based on this class, sensitivity and specificity analyses showed an adequate empirical cut-off point of 75 (out of 100). It is concluded that the Spanish version of the IGD-20 Test is valid and reliable and can be used in research into IGD among Spanish speaking populations
Working Memory Cells' Behavior May Be Explained by Cross-Regional Networks with Synaptic Facilitation
Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex
Psychopolitics: Peter Sedgwick’s legacy for mental health movements
This paper re-considers the relevance of Peter Sedgwick's Psychopolitics (1982) for a politics of mental health. Psychopolitics offered an indictment of ‘anti-psychiatry’ the failure of which, Sedgwick argued, lay in its deconstruction of the category of ‘mental illness’, a gesture that resulted in a politics of nihilism. ‘The radical who is only a radical nihilist’, Sedgwick observed, ‘is for all practical purposes the most adamant of conservatives’. Sedgwick argued, rather, that the concept of ‘mental illness’ could be a truly critical concept if it was deployed ‘to make demands upon the health service facilities of the society in which we live’. The paper contextualizes Psychopolitics within the ‘crisis tendencies’ of its time, surveying the shifting welfare landscape of the subsequent 25 years alongside Sedgwick's continuing relevance. It considers the dilemma that the discourse of ‘mental illness’ – Sedgwick's critical concept – has fallen out of favour with radical mental health movements yet remains paradigmatic within psychiatry itself. Finally, the paper endorses a contemporary perspective that, while necessarily updating Psychopolitics, remains nonetheless ‘Sedgwickian’
Internet Gaming Disorder treatment: a case study evaluation of four different types of adolescent problematic gamers
Research examining Internet Gaming Disorder (IGD) has grown markedly in recent years. However, research on its psychological treatment is still scarce, especially with respect to efficacy of specific programs. The PIPATIC (Programa Individualizado Psicoterapéutico para la Adicción a las Tecnologías de la Información y la Comunicación) program is a 22-session specialized treatment for adolescents with IGD. The present paper briefly outlines the cases of four treatment-seeking male adolescents aged between 13 and 18 years with different clinical IGD profiles undergoing the treatment. A case study using an A-B-A’ withdrawal design was conducted. After completing the PIPATIC program, all participants showed clinical improvement in the amount of time spent using video games and in the symptoms of IGD. Results also demonstrated they received lower scores on clinical tests related to comorbid disorders. In an area with so few studies relating to IGD treatment, the present study is of existential value and contributes clinical information concerning the treatment of IGD in treatment-seeking adolescent patients
ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—Summary Article A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines) 11This document was approved by the American College of Cardiology Foundation Board of Trustees in September 2002, the American Heart Association Science Advisory and Coordinating Committee in August 2002, and the North American Society for Pacing and Electrophysiology in August 2002.22The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur. The conflict of interest information for the writing committee members is posted on the ACC, AHA, and NASPE Web sites with the full-length version of the update.33When citing this document, the ACC, the AHA, and NASPE would appreciate the following citation format: Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol2002;40:1703–19.44Copies: This document is available on the World Wide Web sites of the ACC (www.acc.org) and the AHA (www.americanheart.org). A single copy of the complete guidelines is available by calling 800-253-4636 (US only) or writing the American College of Cardiology, Resource Center, 9111 Old Georgetown Road, Bethesda, MD 20814-1699 (ask for No. 71-0237). To obtain a copy of the Summary Article, ask for reprint No. 71-0236. To purchase additional reprints (specify version and reprint number): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4426, fax 410-528-4264, or e-mail [email protected](J Am Coll Cardiol 2002;40:1703–19.)66©2002 by the American College of Cardiology Foundation and the American Heart Association, Inc.
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