tbuckley/cabot-search huggingface dataset:
<i>In vivo</i> imaging biomarkers of neuroinflammation in the development and assessment of stroke therapies - towards clinical translation
Authors: Bastian Zinnhardt, Maximilian Wiesmann, Lisa Honold, Cristina Barca, Michael Schäfers, Amanda J Kiliaan, Andreas H Jacobs
Journal: Theranostics (2018)

Modulation of the inflammatory microenvironment after stroke opens a new avenue for the development of novel neurorestorative therapies in stroke.Understanding the spatio-temporal profile of (neuro-)inflammatory imaging biomarkers in detail thereby represents a crucial factor in the development and application of immunomodulatory therapies.The early integration of quantitative molecular imaging biomarkers in stroke drug development may provide key information about (i) early diagnosis and follow-up, (ii) spatio-temporal drug-target engagement (pharmacodynamic biomarker), (iii) differentiation of responders and non-responders in the patient cohort (inclusion/exclusion criteria; predictive biomarkers), and (iv) the mechanism of action.The use of targeted imaging biomarkers for may thus allow clinicians to decipher the profile of patient-specific inflammatory activity and the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in stroke.Here, we highlight the recent developments in preclinical and clinical molecular imaging biomarkers of neuroinflammation (endothelial markers, microglia, MMPs, cell labeling, future developments) in stroke and outline how imaging biomarkers can be used in overcoming current translational roadblocks and attrition in order to advance new immunomodulatory compounds within the clinical pipeline.
Effects of immune checkpoint inhibitors on B cells: relationship to immune-related adverse events
Authors: David S Pisetsky
Journal: Annals of the Rheumatic Diseases (2018)

Immune checkpoint inhibitors (ICI) are remarkable agents that represent a revolutionary approach to treat cancer. Rather than directly killing tumour cells, ICIs inhibit the regulatory pathways that prevent a T cell response to the tumour. With checkpoints blocked and T cells free to act, the tumour becomes a target for cytotoxic T cells. ICIs interdict key costimulatory systems involved in checkpoint regulation, binding to either cytotoxic T lymphocyte associated antigen 4 (CTLA-4) or the programme cell death 1 (PD-1) molecule or its ligand, PD-1L. These antibodies can be used either alone or in combination.1 

In view of the effects of ICIs on T cell regulation, this form of therapy is associated with considerable toxicity and a wide variety of immune-related adverse events (irAE). The nature and frequency of these effects vary among agents and include effects on the gastrointestinal tract (colitis), liver, lung (pneumonitis), skin (rash and pruritus) and endocrine glands including hypophysitis. Since CTLA-4 and PD-1 systems involve different lymphocyte populations and act at different sites, the combination shows a broader range of side effects and an increasing frequency.2 

For the rheumatologist, the use of …
The Role of Exportin-5 in MicroRNA Biogenesis and Cancer
Authors: Ke Wu, Juan He, Wenchen Pu, Yong Peng
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract MicroRNAs (miRNAs) are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs (pre-miRNAs) from the nucleus to the cytoplasm by exportin-5 (XPO5). Given the critical role of nuclear export of pre-miRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pin1 impair XPO5′s nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregulation of XPO5 in human tumors.
PD-L1 expression and immune infiltrates in sarcoma.
Authors: Sandra P. D'Angelo, Alexander Noor Shoushtari, Narasimhan P Agaram, Deborah Kuk, Li-Xuan Qin, Richard D. Carvajal, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Gary K. Schwartz, William D. Tap
Journal: Journal of Clinical Oncology (2014)

10522 Background: Programmed death-1 (PD-1) is a member of the CD28 family of T-cell costimulatory receptors that attenuates immune responses by negatively regulating T-cell proliferation and function. The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) has been described in multiple malignancies but are unknown in sarcoma. We previously demonstrated PD-L1 expression by western blot and flow cytometry in 65% of sarcoma cell lines. We now examined PD-L1 expression by IHC in sarcoma specimens and tumor-associated immune cells and correlated expression with clinical parameters and outcomes. Methods: 50 sarcoma patients treated at Memorial Sloan Kettering Cancer Center who were consented to our IRB approved tissue procurement protocol were selected. Correlative clinical information was collected.Using the DAKO PD-L1 IHC assay and archival formalin-fixed paraffin embedded tissue specimens; PD-L1 expression was examined. Positive was defined as >1% of tumor cells (minimum of 100 evaluable cells) with plasma membrane staining. Staining intensity was not used to define positivity. Macrophage (M) and lymphocyte (L) PD-L1 status was determined qualitatively. Associations between PD-L1 expression in tumor, M and L and clinical-pathological characteristics were performed. Results: Median age 46 years (range, 22 - 76), 66% male. Disease status: 70% primary disease/locally recurrent, 26% metastatic and 4% unknown. Tumor, L and M PD-L1 expression was noted in 12%, 30% and 58%, respectively. L and M infiltration was present in 98% and 90%, respectively. There was no association between clinical features, overall survival and PD-L1 expression in tumor or immune infiltrates. Conclusions: L/M infiltration is common in sarcoma. PD-L1 tumor expression is uncommon with the highest frequency observed in GIST. There was no association between PD-L1 expression and OS. Forthcoming studies include a characterization of the immune infiltrates and expansion to additional tumor specimens. Histology n % Tumor PD-L1 + % L PD-L1 + % M PD- L1 + Angiosarcoma 3 0 100 100 GIST 14 27 100 100 Leiomyosarcoma 4 0 0 25 Liposarcoma 5 0 20 60 Synovial Sarcoma 3 0 33 0 Radiation associated pleomorphic sarcoma 1 100 100 100 Other 20 5 10 70 Overall 50 12 30 58
Identifying post-traumatic stress disorder in forced migrants
Authors: Manpreet Bains, Clare Shortall, Tabitha Manzuangani, Cornelius Katona, Katherine Russell
Journal: BMJ (2018)

### What you need to know

A 35 year old man, who was recently forced to migrate because of conflict, presents with headaches. Tension headache is diagnosed and review is arranged. On return he reports that the headaches are relieved by the analgesics he was prescribed, but his sleep is poor and he has frequent nightmares, from which he wakes feeling anxious and sweating.

People who have had to undergo forced migration are more likely to have experienced the sort of trauma that would predispose them to post-traumatic stress disorder (PTSD), and are therefore at higher risk of PTSD than the general population in their new country of settlement.1 However, identifying PTSD is often difficult because vulnerable patients can be reluctant to discuss the details of these traumas without having already established trusting relationships with their doctors.

### Establish whether there are risk factors for PTSD

If a forced migrant describes specific symptoms of PTSD or symptoms of depression, anxiety, anger, drug misuse, or alcohol misuse, ask sensitive questions about their experience and the events leading up to their forced migration to establish if there is …
Reply to Christian Seitz's Letter to the Editor re: Zhangqun Ye, Guohua Zeng, Huan Yang, et al. Efficacy and Safety of Tamsulosin in Medical Expulsive Therapy for Distal Ureteral Stones with Renal Colic: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. Eur Urol 2018;73:385–91.
Authors: Zhangqun Ye, Guohua Zeng, Zhiqiang Chen, Hua Xu
Journal: European Urology (2018)
<i>BRCA1</i> and <i>BRCA2</i> gene mutations and colorectal cancer risk: Systematic review and meta-analysis.
Authors: Mok Oh, Ali McBride, Seongseok Yun, Sandipan Bhattacharjee, Marion Slack, Joanne M. Jeter, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

605 Background: The risks of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations are well established. Investigations of the association of BRCA mutations and the risk of colorectal cancer(CRC) have yielded conflicting results. We performed a systematic review of published and unpublished studies evaluating BRCA and CRC risk, and meta-analyses to quantify overall CRC risk and in subgroups of BRCA mutation carriers. Methods: Eligible studies were retrieved from PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation &amp; Theses. Unadjusted odds ratios were used to derive pooled estimates of CRC risk overall (combined BRCA1/BRCA2) and in subgroups defined by mutation type, comparison group, and study design. Both fixed and random effects models were estimated with the latter having priority. We followed the guidelines summarized in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as well as the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statements. Results: A total of 18 studies were included in the systematic review: 7 cohort studies comparing to the general population, 5 case-control studies, 4 cohort studies involving pedigree analysis, and 2 kin-cohort studies. Fourteen studies included in the systematic review were used in the meta-analysis. The overall BRCA1/BRCA2 meta-analysis revealed an increased CRC risk in a fixed-effects (OR = 1.22, 95%CI = 1.01-1.48, p = 0.041, I 2 = 19.5%) but not in a random-effects model (OR = 1.20, 95%CI = 0.96-1.50, p = 0.111). In subgroup random-effects meta-analyses, BRCA1 was associated with increased CRC risk (OR = 1.48, 95%CI = 1.13-1.94, p = 0.005, I 2 = 3.7%) but BRCA2 was not. Analyses stratified by study design and comparator found no association between BRCA mutation and CRC risk (all 95%CIs crossing 1, all p &gt; 0.05). Conclusions: Although studies differed in their findings about the association between BRCA mutations and CRC risk, meta-analyses revealed a potential 1.22-fold greater risk of CRC in BRCA mutation carriers. This elevated CRC risk was attributable largely to a 1.48-fold greater risk in BRCA1 mutation but not in BRCA2 carriers, regardless of age.
Neutrophil-to-Lymphocyte Ratio Associates Independently With Mortality in Hospitalized Patients With Cirrhosis
Authors: Jonathan Rice, Jennifer L. Dodge, Kiran M. Bambha, Jasmohan S. Bajaj, K. Rajender Reddy, Jane Gralla, Dinesh Ganapathy, Robert Mitrani, Bradley Reuter, Julia Palecki, Chathur Acharya, Jawaid Shaw, James R. Burton, Scott W. Biggins
Journal: Clinical Gastroenterology and Hepatology (2018)
Tandem bispecific broadly neutralizing antibody — a novel approach to HIV-1 treatment
Authors: Guido Ferrari
Journal: Journal of Clinical Investigation (2018)

The last decade has led to a significant advance in our knowledge of HIV-1 latency and immunity. However, we are still not close to finding a cure for HIV-1. Although combination antiretroviral therapy (cART) has led to increased survival, almost close to that of the general population, it is still not curative. In the current issue of the JCI, Wu et al. studied the prophylactic and therapeutic potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb), BiIA-SG. This bnAb’s breadth and potency were highly effective in protection and treatment settings, as measured by complete viremia control following direct infusion, as well as elimination of infected cells and delay in viral rebound when delivered with a recombinant vector. These observations underscore the need for the clinical development of BiIA-SG for the prevention of HIV-1.
Performance of controlled attenuation parameter (CAP) to assess steatosis in a large prospective multicentre UK study of patients with non-alcoholic fatty liver disease (NAFLD)
Authors: P. Eddowes, M. Allison, E. Tsochatzis, Q. Anstee, D. Sheridan, I.N. Guha, J. Cobbold, V. Paradis, P. Bedossa, P. Newsome
Journal: Journal of Hepatology (2018)
c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells
Authors: Leona Gabryšová, Marisol Alvarez-Martinez, Raphaëlle Luisier, Luke S. Cox, Jan Sodenkamp, Caroline Hosking, Damián Pérez-Mazliah, Charlotte Whicher, Yashaswini Kannan, Krzysztof Potempa, Xuemei Wu, Leena Bhaw, Hagen Wende, Michael H. Sieweke, Greg Elgar, Mark Wilson, James Briscoe, Vicki Metzis, Jean Langhorne, Nicholas M. Luscombe, Anne O’Garra
Journal: Nature Immunology (2018)
Freestanding, Fiber‐Based, Wearable Temperature Sensor with Tunable Thermal Index for Healthcare Monitoring
Authors: Tran Quang Trung, Hoang Sinh Le, Thi My Linh Dang, Sanghyun Ju, Sang Yoon Park, Nae‐Eung Lee
Journal: Advanced Healthcare Materials (2018)

Fiber-based sensors integrated on textiles or clothing systems are required for the next generation of wearable electronic platforms. Fiber-based physical sensors are developed, but the development of fiber-based temperature sensors is still limited. Herein, a new approach to develop wearable temperature sensors that use freestanding single reduction graphene oxide (rGO) fiber is proposed. A freestanding and wearable temperature-responsive rGO fiber with tunable thermal index is obtained using simple wet spinning and a controlled graphene oxide reduction time. The freestanding fiber-based temperature sensor shows high responsivity, fast response time (7 s), and good recovery time (20 s) to temperature. It also maintains its response under an applied mechanical deformation. The fiber device fabricated by means of a simple process is easily integrated into fabric such as socks or undershirts and can be worn by a person to monitor the temperature of the environment and skin temperature without interference during movement and various activities. These results demonstrate that the freestanding fiber-based temperature sensor has great potential for fiber-based wearable electronic platforms. It is also promising for applications in healthcare and biomedical monitoring.
415M2 cardiac macrophages in wound healing following myocardial infarction: translation to clinic
Authors: A Gombozhapova, Y Rogovskaya, M Rebenkova, J Kzhyshkowska, V Ryabov
Journal: Cardiovascular Research (2018)

Background: Atherosclerosis development is enhanced by both local and systemic immune responses and mast cells have been shown to accumulate inside atherosclerotic plaques where these cells can degranulate and contribute to disease progression.Our research focused on pathways via which mast cells can elicit their atherogenic effects, such as by shaping the adaptive immune reaction through a direct interaction with CD4þ T-cells.In this study, we thus aimed to analyze the interplay between mast cells and CD4þ T-cells in atherosclerosis.Methods: and Results: In LDLr-/-mice fed a Western-type diet (WTD), the MHC-IIþ/ FceRIaþCD117þ mast cell population in the peritoneum increased significantly (0 wk-WTD:30.461.7%; 4 wk-WTD:52.565.9%,P¼0.01).To examine the efficacy of the MHC-II expressing mast cells in vivo, we injected i/p the Ea-peptide (1mg/mL), which is specifically presented by MHC-II molecules.After 24 hours, we detected Ea-peptide fragments on the peritoneal mast cell surface (PBS:2.360.2%;Ea:7.461.7%;P¼0.02).Interestingly, we also observed that bone marrow derived mast cells (BMMCs) treated in vitro with 10% serum of LDLr-/-mice fed a WTD diet for 4 weeks, showed enhanced MHC-II expression on their surface (chow-MCs: 3.160.3%vs WTD-MCs: 10.2560.1%,P<0.0001).To further investigate the effect of hyperlipidemia in the antigen presentation capacity of mast cells to CD4þ T-cells, we made use of the Ovalbumin presentation system by which CD4þ T-cells from genetically modified OT-II mice can specifically respond to OVA-peptide (OVAp) fragments.Therefore, we co-cultured OVAp-pretreated (10lm/mL) BMMCs under either chow or WTD serum conditions, with OT-II CD4þ T-cells, previously activated by aCD3/aCD28.The proliferation rate of CD4þ T-cells was markedly increased in the WTD condition as measured by [3H]-Thymidine incorporation, (chow-MC: 903362222 dpm compared to WTD-MC: 2533262889 dpm, P<0.0001).Conversely, the aortic CD4þ content of mast cell deficient mice on WTD, showed a reduction in ki67þ/CD4þ proliferation (apoE-/-: 30.965.2% vs apoE/KitW-sh/W-sh: 13.161.2%;P¼0.006) with a pronounced decline in the number of TH1 T-betþ/CD4þ T-cells (apoE-/-:148.4624.5 cells; apoE/KitW-sh/W-sh:45.1616.4cells, P¼0.004).Of clinical relevance, upon examination of 20 human plaques obtained by endarterectomy surgery, we observed that 18.564.4% of human mast cells express HLA-DR (the human equivalent of MHC-II) suggesting that mast cells may be capable of antigen presentation inside the human atherosclerotic plaque. Conclusion:We have increasing evidence that mast cells may function as non-classical antigen presenting cells in atherosclerosis, possibly by influencing the pro-atherogenic TH1 cells inside the plaque microenvironment.Further studies on the role of mast cells as modulators of adaptive immunity may reveal novel means to intercept atherosclerosis development.
Field evaluation of Xpert (Cepheid) Hepatitis C Virus assay for RNA quantification in Genotype 6 predominant patient population in Cambodia
Authors: M. Iwamoto, A. Calzia, S. Yann, S. Pin, C. Lastrucci, S. Kimchamroeun, C. Dimanche, J.-P. Dousset, M.L. Paih, A. Dublineau, S. Balkan, T. Marquardt, J. Nouhin, F. Rouet, A. Loarec, D. Maman
Journal: Journal of Hepatology (2018)
An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides
Authors: Laura L. Eggink, Katherine F. Roby, Robert Cote, J. Kenneth Hoober
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Receptors specific for the sugar <i>N</i>-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response. In this study, we asked whether a peptide that binds in the GalNAc-binding site of CLEC10A would serve as an effective tool to activate an immune response against ovarian cancer. <h3>Methods</h3> A 12-mer sequence emerged from a screen of a phage display library with a GalNAc-specific lectin. The peptide, designated svL4, and a shorter peptide consisting of the C-terminal 6 amino acids, designated sv6D, were synthesized as tetravalent structures based on a tri-lysine core. In silico and in vitro binding assays were developed to evaluate binding of the peptides to GalNAc-specific receptors. Endotoxin-negative peptide solutions were administered by subcutaneous injection and biological activity of the peptides was determined by secretion of cytokines and the response of peritoneal immune cells in mice. Anti-cancer activity was studied in a murine model of ovarian cancer. <h3>Results</h3> The peptides bound to recombinant human CLEC10A with high avidity, with half-maximal binding in the low nanomolar range. Binding to the receptor was Ca<sup>2+</sup>-dependent. Subcutaneous injection of low doses of peptides into mice on alternate days resulted in several-fold expansion of populations of mature immune cells within the peritoneal cavity. Peptide sv6D effectively suppressed development of ascites in a murine ovarian cancer model as a monotherapy and in combination with the chemotherapeutic drug paclitaxel or the immunotherapeutic antibody against the receptor PD-1. Toxicity, including antigenicity and release of cytotoxic levels of cytokines, was not observed. <h3>Conclusion</h3> sv6D is a functional ligand for CLEC10A and induces maturation of immune cells in the peritoneal cavity. The peptide caused a highly significant extension of survival of mice with implanted ovarian cancer cells with a favorable toxicity and non-antigenic profile.
The human gut microbiota: Metabolism and perspective in obesity
Authors: Aline Corado Gomes, Christian Hoffmann, João Felipe Mota
Journal: Gut Microbes (2018)

The gut microbiota has been recognized as an important factor in the development of metabolic diseases such as obesity and is considered an endocrine organ involved in the maintenance of energy homeostasis and host immunity. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT) by allowing the passage of structural components of bacteria, such as lipopolysaccharides (LPS), which activate inflammatory pathways that may contribute to the development of insulin resistance. Furthermore, intestinal dysbiosis can alter the production of gastrointestinal peptides related to satiety, resulting in an increased food intake. In obese people, this dysbiosis seems be related to increases of the phylum Firmicutes, the genus Clostridium, and the species Eubacterium rectale, Clostridium coccoides, Lactobacillus reuteri, Akkermansia muciniphila, Clostridium histolyticum, and Staphylococcus aureus.
Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP)
Authors: Jennifer L. Liang, Tejpratap Tiwari, Pedro Moro, Nancy E. Messonnier, Arthur Reingold, Mark Sawyer, Thomas A. Clark
Journal: MMWR Recommendations and Reports (2018)

This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations and replaces all previously published reports and policy notes; it is intended for use by clinicians and public health providers as a resource. ACIP recommends routine vaccination for tetanus, diphtheria, and pertussis. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with one adolescent booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who have never received Tdap also are recommended to receive a booster dose of Tdap. Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks' gestation, regardless of previous receipt of Tdap. After receipt of Tdap, adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria.