tbuckley/cabot-search huggingface dataset:
DIPG-36. NOVEL THERAPEUTIC APPROACHES USING NANOLIPOSMAL SN-38 FOR THE TREATMENT OF HUMAN BRAINSTEM GLIOMA
Authors: Xingyao He, Nundia Louis, Rintaro Hashizume, Peng Zhang, Irina Balyasnikova, Craig Horbinski, Stewart Goldman
Journal: Neuro-Oncology (2017)

INTRODUCTION: Children with diffuse intrinsic pontine gliomas (DIPGs) die within 2 years after initial diagnosis. The infiltrative nature and anatomic location of DIPGs in an eloquent area of the brain preclude surgical resection, and the blood-brain barrier (BBB) reduces the availability of systemically administered agents. In order to improve outcomes for patients with DIPG, new drug delivery approach circumventing the BBB are greatly needed. Intranasal delivery (IND) is a practical, noninvasive method to deliver therapeutic agents into the brain along with the olfactory and trigeminal nerves pathway. With the advantages of reducing systemic side effects and convenient self-administration for patients, IND is an alternative to systemic (intravenous) and/ or direct invasive (intraparechymal) drug delivery. METHODS: Two human DIPG cells were treated with hydrophobic fluorophore (DiI)–labeled nanoliposomal SN-38. Cell viability was determined by MTS assay and intracellular localization was imaged by confocal microscopy. For in vivo study, mice bearing human brainstem gliomas were randomly assigned to 3 groups: 1. empty nanoliposomes, 2. nanoparticle liposomes containing CPT-11 (nanoliposomal CPT-11), 3. nanoliposomal SN-38, administrating by IND for 3 weeks. In vivo distribution were determined by DiI–labeled nanoliposomal SN-38 into the tumor bearing mice. Tumor growth and response to therapy were quantitatively measured by bioluminescence imaging, and efficacy was assessed by survival analysis. RESULTS: DiI-fluorescence were detected at 30 minutes and peaked at 24 hours following treatment with DiI nanoliposomal SN38. Nanoliposomal SN-38 induced dose dependent inhibition of the growth of DIPG cells, that is greater inhibition than naoliposomal CPT-11. IND of nanliposomal SN38 showed significant reduction of the growth rate in compared to IND of empty nanoliposome. Results from animal survival will be reported at the meeting.
CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions
Authors: Masao Hashimoto, Alice O. Kamphorst, Se Jin Im, Haydn T. Kissick, Rathi N. Pillai, Suresh S. Ramalingam, Koichi Araki, Rafi Ahmed
Journal: Annual Review of Medicine (2018)

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation—many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell–like PD-1 + CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.
Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection
Authors: Barton F. Haynes, Laura P. Hale, Kent J. Weinhold, Dhavalkumar D. Patel, Hua-Xin Liao, Peter B. Bressler, Dawn M. Jones, James F. Demarest, Kristin Gebhard-Mitchell, Ashley T. Haase, John A. Bartlett
Journal: Journal of Clinical Investigation (1999)

Figure 1Immunohistological analysis of the thymus in HIV infection.(a-d) Thymus from HIV-1+ patient no. 1 with no thymopoiesis.(e-h) Thymus from HIV-1 + patient no. 2 with areas of active thymopoiesis.(a) Hematoxylin and eosin stain of patient no.1's lymphoid thymus.×13.(b) A similar area as in a, with thymic epithelium in immunohistological analysis reactive with antikeratin antibody (brown central areas).All keratin + thymic epithelium (e) in the true thymus is collapsed (dark brown areas) and devoid of lymphocytes, with a surrounding infiltrate of blue mononuclear cells present in the thymic perivascular space (P).×13.(c) Immunohistological stain of CD8 + T cells (brown cells; see arrows for examples) in the perivascular space (P) around a central empty thymic epithelial island (e).The dotted line surrounds thymic true epithelial thymus areas (e), and the short arrow points out a rare CD8 + T cell within the true epithelial thymus (e).×66.(d) Many of the perivascular space (P) CD8 + cells are reactive with MAB TIA-1 (arrows) and therefore are mature effector cytotoxic T cells.×66.e-h are from patient no.2's thymus.×33.(e) Light microscopic view of patient no.2's thymus (hematoxylin and eosin stain with a Hassall's body [h] in the thymus medulla).(f) Immunohistological analysis with antikeratin antibody, with areas of normal-appearing keratin + thymic epithelium (brown areas) filled with lymphocytes (blue areas) intermingled with thymic epithelium (arrows).Most developing thymocytes are CD3 + T cells (arrows in g), many of which are normal CD1a + cortical thymocytes (brown cells, arrows in h).A subset of these CD1a + , CD3 + immature thymocytes were actively dividing as determined by nuclear reactivity with MAB mib-1 (not shown).MAB, monoclonal antibody.
Discerning Risk of Disease Transition in Relatives of Systemic Lupus Erythematosus Patients Utilizing Soluble Mediators and Clinical Features
Authors: Melissa E. Munroe, Kendra A. Young, Diane L. Kamen, Joel M. Guthridge, Timothy B. Niewold, Karen H. Costenbader, Michael H. Weisman, Mariko L. Ishimori, Daniel J. Wallace, Gary S. Gilkeson, David R. Karp, John B. Harley, Jill M. Norris, Judith A. James
Journal: Arthritis & Rheumatology (2016)

Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential for curtailing irreversible inflammatory damage. The aim of this study was to identify factors associated with transition to classified disease that would inform our understanding of the risk of SLE.
The catalase gene promoter and 5ʹ-untranslated region variants lead to altered gene expression and enzyme activity in vitiligo
Authors: M.S. Mansuri, S.D. Jadeja, M. Singh, N.C. Laddha, M. Dwivedi, R. Begum
Journal: British Journal of Dermatology (2017)

Background Oxidative stress is considered to be the initial event in the course of vitiligo. The enzyme catalase (CAT) is mainly involved in cellular defence against oxidizing agents through detoxifying H2O2. Objectives The aims were (i) to assess erythrocyte CAT enzyme activity and lipid peroxidation (LPO) levels as well as CAT mRNA expression in skin and blood; (ii) to investigate CAT gene promoter rs7943316, rs1001179, 5ʹ‐untranslated region rs1049982, and exon (rs17886350, rs11032709, rs17880442, rs35677492) polymorphisms; and (iii) to perform genotype/haplotype–phenotype correlation analyses in patients with vitiligo and controls from Gujarat. Methods CAT activity and LPO levels were measured spectrophotometrically. CAT mRNA levels were estimated using real‐time polymerase chain reaction (PCR) by the SYBR Green method. Single‐nucleotide polymorphism genotyping was performed using PCR–restriction fragment length polymorphism and amplification‐refractory mutation system–PCR analyses. Results Patients with vitiligo showed significantly decreased CAT mRNA expression in lesional and nonlesional skin and in blood, with reduced CAT activity compared with that of controls. CAT –89A/T and –20T/C polymorphisms were significantly associated with patients, especially with active and generalized vitiligo, whereas no association was observed for –262G/A and exon polymorphisms. The A–262T–89C–20 haplotype with variant alleles was found to be associated with 6·4‐fold risk of vitiligo. Genotype/haplotype–phenotype correlation analyses revealed that individuals with susceptible genotypes/haplotype for CAT –89A/T and –20T/C polymorphisms showed significantly decreased CAT mRNA/activity, and only –89A/T polymorphisms showed significantly increased LPO levels compared with wild‐type genotypes/haplotype. Conclusions The present study proposes the crucial role of CAT and its allelic variants in oxidative stress‐mediated pathogenesis of vitiligo.
Exposure to rotational acceleration over the course of one athletic season is related to impairments in an index of dynamic cerebral autoregulation
Authors: Alexander D Wright, Jonathan D Smirl, Michael Jakovac, Sarah K Fraser, Kelsey Bryk, Harjas S Grewal, Jill Dierijck, Paul van Donkelaar
Journal: British Journal of Sports Medicine (2017)

Objective To examine the relationship between cerebral autoregulation changes and impact exposuresthroughout a season of contact sports (hockey or football). Design Prospective Cohort. Setting Laboratory. Participants 40 male contact sport athletes (19.4±1.2 years); to date, 3 cross-country athletes (20.0±1.0 years) have completed testing (non-contact controls). Intervention Participants completed testing prior to the start of their athletic seasons (T1), and again after the conclusion of each season (T2). Blood pressure (BP) oscillations were driven by stand-squat manoeuvres at 0.05 and 0.10 Hz. BP and cerebral blood velocity (CBV) in the middle cerebral artery were indexed non-invasively using finger photoplethysmography and transcranial Doppler ultrasound, respectively. RM-ANOVA independent variables included time (2) and frequency (2). Outcome measures Point-estimates of coherence (correlation), phase (synchronisation), and gain (amplitude buffer) transfer function analysis metrics were calculated. Biomechanical data on head-impact exposure was estimated in a subset of contact-sport athletes (n=29) using the xPatch (X2 Biosystems), affixed to the right mastoid. Results Significant frequency-time interaction for gain in contact-sport athletes (p=0.048) but not controls (p=0.213). Simple effects analysis revealed a time effect at 0.10 Hz (p&lt;0.001), whereby gain increased at T2 (95% CI: 0.070–0.229%/%). The Δ gain T2-T1 at 0.10 Hz was correlated withestimated cumulativerotational acceleration exposure (r=0.462, p=0.015). Conclusions These findings suggest cumulative exposure to the rotational component of sustained head-impactsduring participation in a season of contact-sport (hockey or football) impairs the ability of the cerebrovasculature to buffer BP challenges experienced during everyday activities. Competing interests None.
TRTH-20. TREATMENT OF OPTIC PATHWAY GLIOMA AND IMMUNE THROMBOCYTOPENIA (ITP) WITH EVEROLIMUS
Authors: Rohini Singh, Sharon Gardner, Jeffrey Allen
Journal: Neuro-Oncology (2017)

Abstract BACKGROUND: ITP has been described in case reports and a few small series of patients with solid tumors. One possible mechanism of ITP associated with cancer is tumor- induced autoimmunity. CASE DESCRIPTION: A now 15 -year -old female with neurofibromatosis 1 (NF-1) was diagnosed at 6 years of age with an optic pathway glioma. She received treatment with carboplatin and vincristine, and had stable disease for 11 months, until she developed an allergic reaction to carboplatin. At 10 years of age, she exhibited progressive disease and received immunotherapy with three doses of an HLA-restricted peptide vaccine given over 6 weeks. At age 11, she was diagnosed with immune thrombocytopenia, which was controllable with WinRho, and her platelet count remained between 50,000–60,000. At age 14, despite stable MRI findings, she experienced a decrease in visual acuity necessitating further treatment, and Everolimus was instituted. After one year of treatment, her vision has remained stable, and she has a sustained improvement in her platelet count to above 200,000. DISCUSSION/CONCLUSION: There are a number of extenuating factors that may have possibly contributed to the occurrence of ITP, including the emergence of OPG, the allergic reaction to carboplatin, and the prior immunotherapy protocol. Our patient’s decline in visual acuity prompting treatment was closely related temporally to the development of chronic ITP, suggesting the possibility of immune cell dysregulation in both the immune cytopenia and tumor growth. Everolimus, an mTOR inhibitor, has been observed to cause regression of several types of tumors as well as alter immune function and, in a larger series of patients in China, suppress manifestations of ITP. However, this case is unusual in the quick and enduring response of the ITP to Everolimus. This case suggests the efficacy of both the anti-tumor and immunomodulatory effects in Everolimus treatment.
IMMU-32. NON-INFLAMMATORY EFFECT OF DIPG ON TUMOR-ASSOCIATED MICROGLIA
Authors: Grant Lin, Evan Arnold, Christopher Mount, Michelle Monje-Deisseroth
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is a diffusely infiltrating high-grade glioma that has a peak incidence from ages 6-8 and only a 9-12 month median survival. Like adult gliomas, DIPG exhibits a significant expansion of myeloid cells, with microglia/macrophages accounting for ~30% of the tumor cell mass (Caretti & Monje, 2014). In adult glioma, these glioma-associated macrophages have been implicated as supporting angiogenesis and tumor cell invasion, proliferation, and survival (Glass & Synowitz, 2014). However, genomic and epigenomic characterizations of adult and pediatric high-grade gliomas revealed striking differences in the molecular nature of these tumors (Sturm et al., 2014), and traditional chemotherapeutic approaches to adult glioblastoma are not effective in DIPG, suggesting these are unique diseases with distinct pathophysiology. Our data demonstrates that tumor-associated macrophages from primary DIPG samples exhibit gene expression signatures that are associated with pro-tumorigenic functions, but are also significantly less inflammatory than tumor-associated macrophages isolated from adult glioblastoma samples. Moreover, the cytokine secretion profiles of patient-derived DIPG cell cultures are dramatically less inflammatory when compared to patient-derived adult high-grade glioma cell cultures, and are more similar to the profile of human neural precursor cell cultures. This suggests that DIPG is less immunogenic than adult GBM, which may allow the tumor cells to evade detection and infiltrate healthy tissue. We additionally show that DIPG cells express CD200, a ligand that inhibits myeloid cell activation. Knockdown of DIPG expression of CD200 increases primary microglial cell phagocytosis in direct co-culture experiments, and also inhibits DIPG progression in in vivo xenograft models. Thus, CD200 may represent a mechanism by which DIPG evades normal immune responses to tumor growth. By understanding the DIPG-microglial interaction in molecular detail, we will gain insight into the pathophysiology of DIPG that could direct future targeted therapies.
Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis
Authors: Takemichi Fukasawa, Ayumi Yoshizaki, Satoshi Ebata, Kouki Nakamura, Ryosuke Saigusa, Syunsuke Miura, Takashi Yamashita, Megumi Hirabayashi, Yohei Ichimura, Takashi Taniguchi, Yoshihide Asano, Hisashi Shimizu, Yutaka Kazoe, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato
Journal: Arthritis & Rheumatology (2017)

Objective To determine the function and serum levels of soluble forms of programmed death 1 (sPD‐1) and one of its ligands, soluble PD ligand 2 (sPD‐L2), in patients with systemic sclerosis (SSc) and in a mouse model of topoisomerase I (topo I)–induced SSc. Methods Serum levels of sPD‐1 and sPD‐L2 in 91 patients with SSc were examined by enzyme‐linked immunosorbent assay (ELISA). Expression of PD‐1 and PD‐L2 on T cells, B cells, and macrophages was quantified by flow cytometry. The effects of blockade of PD‐1 and PD‐L2 were analyzed by microfluidic ELISA (micro‐ELISA), a technique that can measure very low amounts of cytokines. In addition, the effects of sPD‐1 and sPD‐L2 on disease progression were assessed in mice with topo I–induced SSc. Results Serum levels of sPD‐1 and sPD‐L2 were elevated in patients with SSc and correlated with the extent of fibrosis and immunologic abnormalities. Expression levels of PD‐1 and PD‐L2 were significantly elevated on SSc T cells, B cells, and macrophages. Micro‐ELISA analysis of serum samples from patients with SSc showed that PD‐L2 high B cells had higher levels of interleukin‐10 (IL‐10) production compared with PD‐L2 low B cells, indicating that PD‐L2 acts as a regulator of T cell cytokine production via cognate interactions with T cells and B cells. In mice with topo I–induced SSc, production of IL‐10 by topo I–specific B cells in cultures with T cells and topo I protein was significantly higher than that by conventional B cells, and intraperitoneal injection of recombinant chimeric PD‐1‐Fc and PD‐L2‐Fc canceled these enhanced effects. Conclusion These results suggest that sPD‐1 and sPD‐L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells.
Skin and Vascular Disease—Inside-Out/Outside-In
Authors: Calum A. MacRae
Journal: JAMA Cardiology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
Authors: Norihiro Goto, Taro Ueo, Akihisa Fukuda, Kenji Kawada, Yoshiharu Sakai, Hiroyuki Miyoshi, Makoto Mark Taketo, Tsutomu Chiba, Hiroshi Seno
Journal: Cancer Research (2017)

Abstract Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSCs and intestinal tumors. Lineage-tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5+ or Bmi1+ NSCs resulted in loss of self-renewal but did not perturb homeostasis. Furthermore, in Lgr5+ NSC, deletion of Hes1 and β-catenin stabilization limited tumor formation and prolonged host survival. Notably, in Lgr5+ or Dclk1+ tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSCs and CSCs, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target. Cancer Res; 77(13); 3442–54. ©2017 AACR.
Case 16-2017 — A 69-Year-Old Woman with Urinary Incontinence
Authors: Jason D. Wright, John O. Schorge, Aoife Kilcoyne, Rosemary H. Tambouret
Journal: New England Journal of Medicine (2017)

A 69-year-old woman with a history of superficial bladder cancer presented with persistent urinary incontinence. She had an enlarged uterus, and serial imaging studies showed an enlarging uterine mass lesion with complex features. A diagnostic procedure was performed.
Blood-brain barrier pericyte importance in malignant gliomas: what we can learn from stroke and Alzheimer’s disease
Authors: Sadhana Jackson, Ayman ElAli, Daniela Virgintino, Mark R Gilbert
Journal: Neuro-Oncology (2017)

The pericyte, a constitutive component of the central nervous system, is a poorly understood cell type that envelops the endothelial cell with the intended purpose of regulating vascular flow and endothelial cell permeability. Previous studies of pericyte function have been limited to a small number of disease processes such as ischemic stroke and Alzheimer's disease. Recently, publications have postulated a link between glioma stem cell differentiation and pericyte function. These studies suggest that there may be an important interaction of pericytes with tumor cells and other components of the tumor microenvironment in malignant primary glial neoplasms, most notably glioblastoma. This potential cellular interaction underscores the need to pursue more investigations of pericytes in malignant brain tumor biology. In this review, we summarize the functional roles of pericytes, particularly focusing on changes in pericyte biology during response to immune cells, inflammation, and hypoxic conditions. The information presented is based on the available data from studies of pericyte function in other central nervous system diseases but will serve as a foundation for research investigations to further understand the role of pericytes in malignant gliomas.
What is a gesture? A lesson from comparative gesture research
Authors: Katja Liebal
Journal: Behavioral and Brain Sciences (2017)

Abstract Research into nonhuman primates’ gestures is often limited by the lack of clear criteria to define a gesture and by studying gestures separately from other communicative means. Despite the fundamental differences between the gestural communication of humans and other primates, I argue that sign language research might benefit from the lessons learned from these drawbacks and the current developments in primate communication research.