tbuckley/cabot-search huggingface dataset:
Microneedle delivery of autoantigen for immunotherapy in type 1 diabetes
Authors: Xin Zhao, James C. Birchall, Sion A. Coulman, Danijela Tatovic, Ravinder K. Singh, Li Wen, F. Susan Wong, Colin M. Dayan, Stephanie J. Hanna
Journal: Journal of Controlled Release (2015)

Antigen specific immunotherapy mediated via the sustained generation of regulatory T cells arguably represents the ideal therapeutic approach to preventing beta cell destruction in type 1 diabetes. However, there is a need to enhance the efficacy of this approach to achieve disease modification in man. Previous studies suggest that prolonged expression of self-antigen in skin in a non-inflammatory context is beneficial for tolerance induction. We therefore sought to develop a dry-coated microneedle (MN) delivery system and combine it with topical steroid to minimise local inflammation and promote prolonged antigen presentation in the skin. Here we show that a combination of surface-modified MNs coated with appropriate solvent systems can deliver therapeutically relevant quantities of peptide to mouse and human skin even with hydrophobic peptides. Compared to conventional "wet" intradermal (ID) administration, "dry" peptide delivered via MNs was retained for longer in the skin and whilst topical hydration of the skin with vehicle or steroid accelerated loss of ID-delivered peptide from the skin, MN delivery of peptide was unaffected. Furthermore, MN delivery resulted in enhanced presentation of antigen to T cells in skin draining lymph nodes (LNs) both 3 and 10 days after administration. Repeated administration of islet antigen peptide via MN was effective at reducing antigen-specific T cell proliferation in the pancreatic LN, although topical steroid therapy did not enhance this. Taken together, these data show auto-antigenic peptide delivery into skin using coated MNs results in prolonged retention and enhanced antigen presentation compared to conventional ID delivery and this approach may have potential in individuals identified as being at a high risk of developing type 1 diabetes and other autoimmune diseases.
Automatic respiratory scoring, reality or illusion?
Authors: Cláudia Pereira, Susana Moreira, Dina Grencho, Dina Escaleira, Richard Staats, João Valença
Journal: European Respiratory Journal (2013)

Introduction:The need to reduce costs associated with sleep studies and its visual staging, as well as variability in intra-and interindividual scoring, has reasoned demand intense algorithms that allow automatic staging credible.  Aim:Evaluate the analysis and quantification of automatic respiratory scoring of the Alice5-Philips Respironics compared to conventional manual system,using the rulesAASM 2007.  Methods:We analyzed34studies.Each record was subjected to 4avaliations:Av1-Alice5PSGautomatic Analize;Av2-Alice5Automatic Analyze without EEG-cardio-respiratory regist(CRR);Av3-CCRmanual scoring;AV4-manual PSG scoring. Statistical analysis was performed using SPSS.Was considered a level of significance of 95%.  Results:We found significant differences inAHI between assessmentsAv1-AV4andAV4-Av3,with in the opposite resultAv2-AV4.When comparing the avaluationsAv1-AV4we found significant differences in the number of obstructive/central and mixed and hypopneias without significant changes in the total number of apneas.There are significant differences in the desaturation index when comparing Av1,Av2andAv3 toAV4.As forIDR,there are significant differences when compared the 4avalitations.  Conclusions/Discussion:In our analysis it was found that the automatic staging presented numerous flaws, the most significant difference are present at the classification of the apneas type on par with sub-accounting of hypopneas. This difference between automatic and visual staging may affect the decision between treating or not a patient with positive pressure, or even, the choice of ventilation mode.
Addressing End-of-Life Quality Gaps in Hematologic Cancers
Authors: Thomas W. LeBlanc
Journal: JAMA Internal Medicine (2015)

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 Internal Medicine 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 Internal Medicine journal
Spectrum of EGFR mutations associated with non-small cell lung cancer in an Asian Chinese population
Authors: C. Wong, W. Chan, H. Lam, W. Chan, L. Wang, E. Ma
Journal: Journal of Clinical Oncology (2006)

20055 Background: Somatic mutations in tyrosine kinase (TK) domain of the EGFR gene, predicting for sensitivity to TK inhibition therapy, are over-represented in lung cancer with adenocarcinoma or bronchioloalveolar histology, non-smokers, female gender and East Asian ethnicity. Methods: We prospectively screened for EGFR mutations at exons 19–21 on micro-dissected specimen enriched for tumor cells by direct nucleotide sequencing in Hong Kong Chinese patients. Results: From May 2005 onwards, a total of 27 patients were analyzed. They comprised 11 males and 16 females with a median age of 67 years. Histological diagnoses were adenocarcinoma (n = 22), bronchioloalveolar carcinoma (n = 4) and squamous cell carcinoma (n = 1). Samples included primary tumor (n = 20) as well as metastatic lesions (n = 7). EGFR mutations were detected in 17 patients (63%), the most common being L858R at exon 21 (n = 7) followed by exon 19 deletions (del(746–750) = 3, del(747–751) = 1, del(747–753) = 3) and G719C at exon 18 (n = 1). Two patients showed novel EGFR mutations, namely 4-base pair insertion deletion at exon 19 leading to substitution of Glu746-Leu747 by Val746-Pro747 and three base pair deletion at exon 18 leading to replacement of Glu709-Thr710 by Asp. Furthermore, two patients showed double mutations, including novel S768I at exon 20 in combination with G719C, and novel K860I at exon 21 in combination with L858R. Finally, one patient showed homozygous del(747–753) as detected by sequencing in both primary lung tumor and brain secondary, which might represent loss of heterozygosity. Conclusions: Similar to other series, two hotspots i.e. exon 19 deletion and L858 account for the majority (82%) of detectable EGFR mutations in our patient population. For the rare and novel variants, it would be of interest to document the clinical responsiveness to TK inhibitors gefitinib and erlotinib, so that a more complete picture of cancer genotype phenotype correlation can be achieved. No significant financial relationships to disclose.
Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no‐treatment study
Authors: Michael Loschi, Raphael Porcher, Fiorenza Barraco, Louis Terriou, Mohamad Mohty, Sophie de Guibert, Beatrice Mahe, Richard Lemal, Pierre‐Yves Dumas, Gabriel Etienne, Fabrice Jardin, Bruno Royer, Dominique Bordessoule, Pierre Simon Rohrlich, Luc Mathieu Fornecker, Celia Salanoubat, Sebastien Maury, Jean‐Yves Cahn, Laure Vincent, Thomas Sene, Sophie Rigaudeau, Stephanie Nguyen, Anne‐Claire Lepretre, Jean‐Yves Mary, Bernadette Corront, Gerard Socie, Regis Peffault de Latour
Journal: American Journal of Hematology (2015)

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (&gt;2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1–10]) as compared to the historical cohort (27% [20–34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution. Am. J. Hematol. 91:366–370, 2016. © 2016 Wiley Periodicals, Inc.
The effect of smoking cessation on methacholine responsiveness in young asthma patients
Authors: Christian Westergaard, Celeste Porsbjerg, Vibeke Backer
Journal: European Respiratory Journal (2013)

Background: Smoking in asthma patients constitutes a major health problem. Asthma patients who smoke expericence more pronounced asthma disease, but whether this is reversible is largely unknown. We hypothesized that the bronchial reactivity to methacholine in young asthma patients would decrease over a short term of 5 weeks of smoking cessation. Thus, the aim of the present study was to evaluate the effect of smoking cessation on the dynamics of airway reactivity to methacholine in young asthma patients.

Material and methods: 44 steroid-free asthmatic smokers (age 19-40) were examined with methacholine challenges, spirometry and Asthma Control Questionnaire score one week before and and five weeks after a smoking cessation attempt. Mean number of packyears was 16.0 (range 10-25). Asthma diagnosis was confirmed with clinical interview and one or more positive clinical tests indicative for asthma.

Results: Of 44 smokers, 25 patients quit smoking successfully. The proportion of subjects with airway hyperresponsiveness (AHR) to methacholine decreased from 76% to 48% (p=0.016) after quitting, whereas AHR among continuous smokers was unchanged (70% and 65%, respectively, p=1.000). The response to methacholine decreased in the quitter group (Dose-response ratio (RDR): geometric mean 9.35 to 5.97 (p=0.013)), whereas it was unchanged in the non-quitters (8.37 to 6.83 (p=0.430)).

Conclusion: Our data indicates that smoking cessation in asthma patients rapidly improves the bronchial responsiveness, a key feature of asthma, stressing the importance of smoking cessation in this group of patients. The results of the present study may contribute to increasing the motivation of asthmatics to quit smoking.
Subset analysis of the safety and efficacy of nivolumab in elderly patients with metastatic melanoma
Authors: Morganna Freeman, Jeffrey Weber
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Cancer immunotherapy has generated significant response rates and prolonged survival, particularly in metastatic melanoma, but carries the risk of immune-related adverse events (irAEs) [1]. Treatment of elderly patients with checkpoint inhibition presents a unique challenge as
Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi
Authors: Francesco Merli, Stefano Luminari, Paolo G. Gobbi, Nicola Cascavilla, Caterina Mammi, Fiorella Ilariucci, Caterina Stelitano, Maurizio Musso, Luca Baldini, Sara Galimberti, Francesco Angrilli, Giuseppe Polimeno, Potito Rosario Scalzulli, Angela Ferrari, Luigi Marcheselli, Massimo Federico
Journal: Journal of Clinical Oncology (2015)

Purpose The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years. Patients and Methods Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months). Results The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively). Conclusion With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.
The politics of global health security
Authors: Lawrence O Gostin
Journal: The Lancet (2015)

Disease Diplomacy by Sara Davies, Adam Kamradt-Scott, and Simon Rushton delves into the high politics of global health security. They trace this new disease diplomacy to the severe acute respiratory syndrome (SARS) epidemic of 2003. Ever since that time, and indeed long before, political leaders took notice of the security and economic effects of new infections spanning national borders.
Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC)
Authors: H. S. Rugo, M. Campone, D. Amadori, A. Wardley, E. Villa, P. F. Conte, B. Mudenda, B. McHenry, X. Pivot
Journal: Journal of Clinical Oncology (2009)

1029 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m 2 IV on days 1, 8 &amp; 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m 2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m 2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1 st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev. [Table: see text] [Table: see text]
Gestational Diabetes Mellitus in Early Pregnancy: Evidence for Poor Pregnancy Outcomes Despite Treatment
Authors: Arianne N. Sweeting, Glynis P. Ross, Jon Hyett, Lynda Molyneaux, Maria Constantino, Anna Jane Harding, Jencia Wong
Journal: Diabetes Care (2015)

Recent guidelines recommend testing at <24 weeks of gestation for maternal dysglycemia in "high-risk" women. Evidence to support the early identification and treatment of gestational diabetes mellitus (GDM) is, however, limited. We examined the prevalence, clinical characteristics, and pregnancy outcomes of high-risk women with GDM diagnosed at <24 weeks of gestation (early GDM) and those with pre-existing diabetes compared with GDM diagnosed at ≥24 weeks of gestation, in a large treated multiethnic cohort.Outcomes from 4,873 women attending a university hospital antenatal diabetes clinic between 1991 and 2011 were examined. All were treated to standardized glycemic targets. Women were stratified as pre-existing diabetes (n = 65) or GDM diagnosed at <12 weeks of gestation (n = 68), at 12-23 weeks of gestation (n = 1,247), or at ≥24 weeks of gestation (n = 3,493).Hypertensive disorders in pregnancy including pre-eclampsia, preterm delivery, cesarean section, and neonatal jaundice (all P < 0.001) were more prevalent in women with pre-existing diabetes and early GDM. Macrosomia (21.8% vs. 20.3%, P = 0.8), large for gestational age (39.6% vs. 32.8%, P = 0.4), and neonatal intensive care admission (38.5% vs. 39.7%, P = 0.9) in women in whom GDM was diagnosed at <12 weeks of gestation were comparable to rates seen in women with pre-existing diabetes.Despite early testing and current best practice treatment, early GDM in high-risk women remains associated with poorer pregnancy outcomes. Outcomes for those in whom GDM was diagnosed at <12 weeks of gestation approximated those seen in pre-existing diabetes. These findings indicate the need for further studies to establish the efficacy of alternative management approaches to improve outcomes in these high-risk pregnancies.
Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
Authors: Cheng Xing, Xing-Xing Lu, Peng-Da Guo, Tong Shen, Shen Zhang, Xiao-Shun He, Wen-Juan Gan, Xiu-Ming Li, Jing-Ru Wang, Yuan-Yuan Zhao, Hua Wu, Jian-Ming Li
Journal: Cancer Research (2015)

Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies.
Effects of oxygen supplementation on cerebral oxygenation during progressive exercise in patients with COPD and healthy controls
Authors: Mayron Faria Oliveira, Miguel Koite Rodrigues, Luciana S. Takara, Erika Cristine Treptow, Thulio M. Cunha, J. Alberto Neder
Journal: European Respiratory Journal (2011)

The rate of change (Δ) in cerebral oxygenation (COx) during exercise is modulated by cerebral blood flow and arterial O 2  content (CaO 2 ). It is currently unclear whether ΔCOx would (i) be impaired during exercise in patients with chronic obstructive pulmonary disease (COPD) who are not overtly hypoxaemic and (ii) improve with hyperoxia (HiOX, FIO 2 = 0.4) in these patients. Twenty non-hypercapnic males with COPD (FEV 1 = 47.2±11.5% predicted) and 9 age- and gender-matched controls underwent incremental exercise tests under HiOX and normoxia (NOX). ΔCOx was determined by near infrared spectroscopy (fold-changes in HbO 2 ) and cardiac output (QT) by impedance cardiography. A significant drop in SpO 2  was found in 8/20 patients (peak SpO 2 = 86±2% vs. 96±2% for “desaturators” (DESAT) and “non-desaturators” (NONDESAT), respectively. In NOX, ΔCOx was lower in DESAT  versus  NONDESAT and controls; in contrast, mean arterial pressure (MAP) was higher in the former group (p 2  with HiOX were particularly pronounced in DESAT (86±2 vs. 99±1%); interestingly, a significant improvement in COx was found only in this group (0.52±0.20 vs. 2.09±0.42; p 2  therapy. O 2  supplementation (FIO 2 = 0.4) is able to correct for these abnormalities, an effect that was related to enhanced CaO 2  rather than improved cerebral haemodynamics.  Supported by: CNPq and FAPESP, Brazil.