Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma

Morphometric Characteristics of the Extreme Eastern Algerian Domestic Donkey (Equus asinus)

The aim of this study was to define the morphometric variability of the extreme Eastern Algerian donkeys. The study was carried out from June to December 2018 in El-Tarf, Souk-Ahras, and Tebessa provinces. The study population involved 65 individuals (32 jacks and 33 jennies) between the ages of 3 and 16 years old. In total, 13 body measurements were used, and 5 zootechnical indexes were calculated. The quantitative and qualitative characteristics were studied in order to establish an ethnic and functional classification of this particular subspecies. The qualitative data demonstrated that the coat colour was variable. Bay and greyish colours were dominant with a respective rate of 61.5 % and 38.5 %, respectively. The head, the nose, as well as the eyes contour colours were mainly grey with 52.3 %, 58.5 % and 50.8 % respectively. The partial absence of the coat particularities was observed. The population presented a significate relationship between the quantitative characters (P < 0.05). The donkeys were longilinear, of a rectilinear profile, compact with massive trends. They had a hyper-metric format. The animals are good for meat production. The General Linear Model (GLM) showed that the body measurements were variable by sex and body mass. The principal component analysis (PCA), the multiple correspondence analyses (MCA) and the ascending hierarchical classification (AHC) revealed that the population was composed of 2 clusters representing 4 animal classes. This study was the first report on the phenotypic characterization of donkeys in the extreme Eastern Algerian area, based on corporal measurements. The results indicated the existence of heterogeneity and suggested the possibilities of genetic improvement within the species

Internalization of Islamic Education Values Through Ruqyah at the Ruqyah Al Hikmat Institute in Sidenreng Rappang Regency

The research entitled Internalization of Islamic Education Values Through Ruqyah at the Ruqyah Al Hikmat Institute in Sidenreng Rappang Regency, aims to: a. Describe the Ruqyah technique applied at the Al Hikmat Ruqyah Institute, b. Describe the process of internalizing Islamic educational values for Ruqyah patients at the Al Hikmat Ruqyah Institute, c. Describe the implications of internalizing Islamic educational values through ruqyah for ruqyah patients at the Al Hikmat Ruqyah Institute. This type of research is field research using qualitative data processing techniques. The research subject is the Internalization of Islamic Education Values and the research object is ruqyah activities carried out at the Rugyah Al Hikmat Institute. Data collection in research includes interviews, observation and documentation. The data collected is carried out by data reduction to select appropriate data, then data interpretation and data presentation are carried out and conclusions are drawn. The research results show; 1) The Ruqyah technique applied at the Al Hikmat Ruqyah Institute includes prayer through the media of water, salt and oil or read directly to the patient, Ruqyah with verses from the Qur'an, Hypnotherapy, motivational advice. 2) The process of internalizing the values of Islamic education for Ruqyah patients at the Al Hikmat Ruqyah Institute includes: The Value Transformation Stage is implemented through a lecture or preaching model involving Aqidah, Morals and Worship. The da'wah is delivered both individually and to audiences such as the patient's family. The da'wah theme is adapted to the patient's needs. The Value Transaction Stage is implemented by establishing two-way communication between the Team, the patient and the patient's family.&nbsp; This communication is not only established directly, but can also be done through other media such as WhatsApp. It can be seen from several observations that Peruqyah has to be patient in listening to his patients' stories and this has an effect on the patient because he can listen to Peruqyah's advice because he feels cared for and never pushed into a corner. The stages of internalization include knowledge and awareness, practice and habituation and characterization of the value of Islamic education in patients.&nbsp; One of the most important factors of internalization is the example that makes an impression on the ruqyah patient so that even without the physical presence of the ruqyah, the preaching and teaching of Islamic values for the patient will continue to be remembered and become a practice which ultimately becomes a character for the patient. 3) This form of internalization has implications on the practice of Islamic values in daily life with full self-awareness and that is part of the characterization that occurs in ruqyah patients, such as there are patients who after recovering no longer leave prayers and even always pray in congregation at the mosque, there are patients who since recovering have not I like to argue or argue with my neighbor

The Pattern of Education on Aqidah, Worship, The morals of the Santri Tassbeh Baitul Qur'an Islamic Boarding School, Pinrang Regency

The problem in this study is that the students do not understand the education of Aqidah, worship, and morals towards themselves. This thesis aims to describe the pattern of education in providing understanding of Aqidah, increasing worship, and forming morals through fostering students in carrying out learning programs at the Tassbeh Baitul Quran Islamic Boarding School, Pinrang Regency. The type of research used is descriptive qualitative research. The approach taken is phenomenology. The data sources of this research are primary and secondary data sources. Methods of data collection by observation, interviews and documentation. Data analysis techniques with non-statistical analysis, namely by collecting, reducing, presenting and drawing conclusions. Testing the validity of the data is by reference, participation and data triangulation. The results of this study are (1) the pattern of education in understanding the Aqidah of Santri at the Tassbeh Baitul Quran Islamic Boarding School, Pinrang Regency, which is carried out with an authoritarian system through the morning halaqah program and routine taklim. (2) Educational Patterns in Improving Santri Worship at the Tassbeh Baitul Quran Islamic Boarding School, Pinrang Regency, namely carried out with an authoritarian system and parenting through the dawn halaqah program, routine taklim, and absence of worship control. 3) The pattern of education in the formation of the morals of the Santri Tassbeh Baitul Quran Islamic Boarding School in Pinrang Regency is carried out with a system of upbringing and character building through a program of implementing rules, special advice, calling parents. The first implication of this research is that future researchers can develop research on educational patterns applied in Islamic boarding schools. Secondly, this educational program can continue to be implemented in Islamic boarding schools, but there is still a need to strengthen the communication between supervisors and parents in managing the program

Argumentaire pour une utilisation plus large de la photochimiothérapie extracorporelle chez l’enfant

International audienceThe management of immune diseases in children remains challenging , although significant advances have been made. In addition to pharmacological approaches, extracorporeal photochemotherapy (ECP) is distinctive in its ability to provide immunomodulation without immune suppression or toxicity. However, in practice, this therapy is not widely used because of logistical issues and the lack of robust clinical pediatric studies. Here, we discuss the potential clinical applications of ECP in children and emphasize the need for a rigorous and specifically pediatric clinical evaluation of ECP. ß 2010 Elsevier Masson SAS. All rights reserved. Résumé Malgré l'apport des biothérapies, le traitement des maladies dysim-munitaires sévères et des conflits allogéniques de l'enfant reste difficile et entaché de nombreuses complications. Dans ce contexte, la photo-chimiothérapie extracorporelle (PCE) (thérapie cellulaire qui repose sur l'effet immunomodulateur des cellules mononucléées du patient, prélevées par aphérèse et exposées ex vivo aux rayons ultraviolets A [UVA] en présence de psoralène) a l'avantage notable d'induire une tolérance immunitaire sans générer d'immunosuppression systémique ni de toxicité a ` court, moyen ou long terme. Cette immunomodulation fait intervenir notamment la génération de lymphocytes T régulateurs (T reg). Malgré cela, la PCE est peu utilisée en raison de ses contraintes logistiques et du manque de données cliniques. Nous proposons une revue des indications reconnues et potentielles de la PCE en pédiatrie. Nous insistons sur la nécessité d'une e ´valuation clinique spécifique a ` l'enfant qui ne peut se concevoir sans la participation active des cliniciens pédiatres en particulier dans le domaine de la transplanta-tion et des maladies auto-immunes et inflammatoires

Preoperative Hypoalbuminemia Predicts Early Mortality Following Open Abdominal Surgery in Patients Above 60 Years of Age

Background: Major abdominal surgery in older and frail patients is associated with considerable morbidity and mortality. Plasma albumin is routinely measured in the clinic and has been proposed as an indicator of frailty. This study aimed to investigate if plasma albumin is a predictor of mortality in older patients undergoing open abdominal surgery. Materials and methods: We conducted a single-center, register-based retrospective study of patients, aged ⩾60 years who underwent one of 81 open abdominal surgical procedures. Patients operated on during the period from January 1st, 2000 to May 31st, 2013 were consecutively identified in the Danish National Patient Registry. Plasma albumin was measured within 30 days prior to surgery and the primary endpoint was 30-day postoperative mortality. Results: 3,639 patients were included of whom 68.2% underwent emergency surgery. The rate of severe hypoalbuminemia (plasma albumin &lt; 28 g/L) was 43.4%. Preoperative plasma albumin was lower in patients with a fatal 30-day outcome (mean 20.6 g/L vs 30.1 g/L in survivors, p &lt; 0.0001). Other independent predictive parameters of 30-day mortality were age, male sex, and emergency surgery. We present an algorithm including these four variables for the prediction of 30-day mortality for patients aged ⩾60 years undergoing open abdominal surgery. Conclusion: Preoperative plasma albumin is a predictor of 30-day mortality in patients above 60 years of age following open abdominal surgery. Assessment of plasma albumin in conjunction with other risk factors such as age, sex, and surgical priority may improve preoperative decision-making. </jats:sec