Oncogene-Targeting T Cells Reject Large Tumors while Oncogene Inactivation Selects Escape Variants in Mouse Models of Cancer

SummaryThe genetic instability of cancer cells frequently causes drug resistance. We established mouse cancer models, which allowed targeting of an oncogene by drug-mediated inactivation or monospecific CD8+ effector T (TE) cells. Drug treatment of genetically unstable large tumors was effective but selected resistant clones in the long term. In contrast, TE cells completely rejected large tumors (≥500 mm3), if the target antigen was cancer-driving and expressed in sufficient amounts. Although drug-mediated oncogene inactivation selectively killed the cancer cells and left the tumor vasculature intact, which likely facilitated survival and growth of resistant clones, TE cell treatment led to blood vessel destruction and probably “bystander” elimination of escape variants, which did not require antigen cross-presentation by stromal cells

Das Tumorsuppressorprotein p14ARF reguliert die Checkpoint Kontrolle des Zellzyklus und induziert Zelltod

The tumour suppressor protein p14ARF is encoded by the human INK4a gene locus and it is known that a mutation of this gene is present in almost half of all cancers. It has been shown that p14ARF plays a unique role in the regulation of cell cycle arrest and apoptosis following oncogenic stress. The aim of this thesis was to investigate the regulation of p14ARF induced cell death. To this end, p53 wild type MCF-7 breast carcinoma cells, which have lost the key executioner caspase-3 and MCF-7 cells stably re-transfected with procaspase-3 were employed. Expression of p14ARF induced a dominant G1 arrest in both caspase-3 deficient mock and caspase-3 re-expressing MCF-7 transfectants, but no cell death. Additional checkpoint abrogation by the kinase inhibitor caffeine was accompanied by loss of cell viability in both caspase-3 and mock transfectants. Regardless of the presence of caspase-3, MCF-7 cells died from the G2 phase of the cell cycle. In caspase-3 proficient MCF-7 cells, p14ARF induced apoptosis (type I cell death) after sensitization with caffeine. This was executed via the mitochondrial pathway as evidenced by a breakdown of the mitochondrial membrane potential, cytochrome c release and caspase activation. In contrast, caspase-3 deficient MCF-7 cells died through a non-apoptotic mechanism that was characterized as autophagy. Inhibition of the DNA damage response by caffeine impaired expression of the CDK inhibitor p21 and this was linked to induction of cell death by p14ARF. Thus, loss of p21 facilitates p14ARF-induced apoptosis in a caspase-3 dependent manner or autophagy in the absence of efficient executioner caspase activation. These data indicate that cell cycle arrest programs interfere with p14ARF-induced apoptosis that strictly depends on caspase-3 and that loss of this executioner caspase facilitates induction of autophagy cell death. The impact of the antiapoptotic Bcl-2 protein on p14ARF-induced apoptosis in combination with caffeine was examined using SW480 cells stably overexpressing Bcl-2 at the endoplasmic reticulum or at the mitochondria. Obtained data clearly showed that only when Bcl-2 was localized at the mitochondria apoptosis was completely blocked. These data provide evidence that after sensitization with caffeine, p14ARF predominantly targets the mitochondria to execute cell death. Another essential objective in this thesis was to propose a new useful tool against radiation resistance MCF-7 cells. Additionally, p14ARF sensitized cells for ionizing irradiation, promoted cell cycle progression, and triggered apoptosis via an entirely caspase-3 dependent pathway.Das INK4a Gen kodiert für das Suppressorprotein p14ARF, welches in fast der Hälfte aller Tumore mutiert ist. Es wurde gezeigt, dass p14ARF eine wichtige Rolle in der Regulation des Zellzyklusarrestes und der Apoptose spielt. Das Ziel dieser Arbeit war es, die Regulation des p14ARF-induzierten Zelltodes zu untersuchen. Aus diesem Grund wurde eine MCF-7 p53 wildtyp Brustkrebs Zelllinie verwendet, welche keine Effektor Caspase-3 exprimiert, sowie MCF-7 Zellen die stabil mit Caspase-3 retransfiziert wurden. Die Expression von p14ARF induzierte einen G1 Arrest, sowohl in Caspase-3 defizienten als auch in Caspase-3 exprimierenden MCF-7 Transfektanten, jedoch konnte kein Zelltod detektiert werden. Eine zusätzliche Behandlung mit dem Kinase Inhibitor Koffein führte zu einem Verlust der Zellviabilität in den Caspase-3 profizienten als auch defizienten MCF-7 Zellen. Die MCF-7 Zellen starben dabei aus der G2 Phase des Zellzykluses heraus, unabhängig von der Caspase-3 Expression. In Caspase-3 exprimierenden MCF-7 Zellen, induzierte p14ARF, nach Sensibilisierung mit Koffein, Apoptose. Die Vermittlung erfolgte über den mitochondrialen Apoptosesignalweg, detektiert durch den Zusammenbruch des mitochondrialen Membranpotentials, der Cytochrom c Freisetzung und der Caspaseaktivierung. Im Gegensatz dazu, starben Caspase-3 defiziente MCF-7 Zellen durch einen nicht apoptotischen Mechanismus, welcher als Autophagie charakterisiert werden konnte. Die durch Koffein ausgelöste Hemmung der Zellantwort auf DNA-Schäden verminderte die Expression des CDK Inhibitors p21, was zu einer Zelltodinduktion durch p14ARF führte. Der Verlust von p21 führte zu einer Caspase-3 anhängigen p14ARF-induzierten Apoptose bzw. zu Autophagy in Abwesenheit einer effizienten Caspaseaktivierung durch den Verlust von Caspase-3. Diese Daten zeigen, dass die Beeinflussung des Zellzyklus entscheidend für die p14ARF-induzierte Apoptose ist, welche von der Expression von Caspase-3 abhängig ist. Der Verlust der Caspase-3 führt zu einem Zelltod der durch Autophagie vermittelt wird. Des Weiteren wurde der Einfluss des anti-apoptotischen Proteins Bcl-2 auf die p14ARF-induzierte Apoptose in Kombination mit Koffein in SW480 Zellen untersucht, die stabil Bcl-2 entweder am Endoplasmatischen Retikulum oder an den Mitochondrien exprimieren. Die Ergebnisse zeigten eindeutig, dass die Überexpression von Bcl-2, die p14ARF- induzierte Apoptose komplett hemmt, jedoch nur, wenn Bcl-2 an den Mitochondrien lokalisiert war. Dies legt den Schluss nahe, dass nach Sensibilisierung mit Koffein, p14ARF vorzugsweise über die Mitochondrien Apoptose induziert. Ein weiteres wichtiges Ziel dieser Arbeit war es, neue brauchbare Therapien für bestrahlungsresistente MCF-7 Zellen zu entwickeln. Hier zeigte sich, dass eine Sensitivierung der Zellen für strahlungsinduzierten apoptotischen Zelltod und eine begünstigte Zellzyklusprogression durch p14ARF von Caspase-3 abhängig ist

Visceral leishmaniasis diagnosis and reporting delays as an obstacle to timely response actions in Nepal and India

Background: To eliminate visceral leishmaniasis (VL) in India and Nepal, challenges of VL diagnosis, treatment and reporting need to be identified. Recent data indicate that VL is underreported and patients face delays when seeking treatment. Moreover, VL surveillance data might not reach health authorities on time. This study quantifies delays for VL diagnosis and treatment, and analyses the duration of VL reporting from district to central health authorities in India and Nepal. Methods: A cross-sectional study conducted in 12 districts of Terai region, Nepal, and 9 districts of Bihar State, India, in 2012. Patients were interviewed in hospitals or at home using a structured questionnaire, health managers were interviewed at their work place using a semi-structured questionnaire and in-depth interviews were conducted with central level health managers. Reporting formats were evaluated. Data was analyzed using two-tailed Mann-Whitney U or Fisher’s exact test. Results: 92 VL patients having experienced 103 VL episodes and 49 district health managers were interviewed. Patients waited in Nepal 30 days (CI 18-42) before seeking health care, 3.75 times longer than in Bihar (8d; CI 4-12). Conversely, the lag time from seeking health care to receiving a VL diagnosis was 3.6x longer in Bihar (90d; CI 68-113) compared to Nepal (25d; CI 13-38). The time span between diagnosis and treatment was short in both countries. VL reporting time was in Nepal 19 days for sentinel sites and 76 days for “District Public Health Offices (DPHOs)”. In Bihar it was 28 days for “District Malaria Offices”. In Nepal, 73% of health managers entered data into computers compared to 16% in Bihar. In both countries reporting was mainly paper based and standardized formats were rarely used. Conclusions: To decrease the delay between onset of symptoms and getting a proper diagnosis and treatment the approaches in the two countries vary: In Nepal health education for seeking early treatment are needed while in Bihar the use of private and non-formal practitioners has to be discouraged. Reinforcement of VL sentinel reporting in Bihar, reorganization of DPHOs in Nepal, introduction of standardized reporting formats and electronic reporting should be conducted in both countries

Katalog edukacija 2015/2016 godine

Since 2010, the Institute for Science Application in Agriculture as the organization authorised by the Ministry of Agriculture and Environmental Protection of the Republic of Serbia has been providing continuous training of advisors from PSSS, in order to improve their knowledge and skills in the field of agriculture. These continuous training courses substantially contribute to the transfer of knowledge and information from advisors to agricultural producers, being carried out to strengthen the competitiveness of agricultural production and increase the quality of agricultural products. Besides agricultural advisors, the trainees are also producers associations, local government, rural development centres, NGOs and other subjects interested in acquiring and improving their knowledge. The trainees receive the Certificate of Training/Education Completion issued by the Institute for Science Application in Agriculture, and this certification is necessary for getting the License for Advisory Work. The training programme is designed based on the need assessment of agricultural advisors and producers as well as on priorities of agriculture and rural development in the Republic of Serbia. The training programmes have been implemented with the help of the funding from the Ministry of Agriculture and Environmental Protection of the Republic of Serbia, as well as through the participation of partner organisations (Institute of Field and Vegetable Crops from Novi Sad, GIZ, SDC), USDA technical assistance, project collaboration (TEMPUS, IPA, FADN). The Institute organises 10 to 20 modules per year. From 2010 to 2016, the Institute carried out 54 modules and 3 workshops, as well as 8 seminars of the Agricultural Advisory Service of the Republic of Serbia. All modules were approved by the Expert Council on Advisory Work and Applied Research of the Ministry of Agriculture and Environmental Protection of the Republic of Serbia. During 2015 and 2016, the Institute with its partners from the TEMPUS project (544072-TEMPUS- 1-2013-1-RS-TEMPUS-SMHES (2013-4604 / 001-001) “Building Capacity of Serbian Agricultural Education to Link with Society (CaSA)” developed and implemented 10 modules. Their special contribution is reflected in the development of modules for distance learning (“e-learning”), aimed to build the capacity of PSSS and the capacity of agricultural education in the Republic of Serbia through modern means of learning. The training courses cover all areas of agricultural production (animal husbandry, field and vegetable crop production, fruit production and viticulture, plant protection, food technology, agricultural economics), as well as production management, EU standards and regulations, rural tourism, rural development, agricultural policy measures and training of advisors on advisory techniques and skills. The task of these training courses is to enable: 1. Modernisation of knowledge, i.e. innovation of knowledge on new and modern production technologies, 2. Extension of knowledge from the areas not covered by regular schooling, and 3. Acquiring of applied knowledge - mastering advisory skills. 5 The training courses are carried out through different types of training: classroom lectures, practical training, distance learning (e-learning) and combined thematic lectures and distance learning (blended). To ensure the quality and practical use of training courses, the Institute carries out the courses in collaboration with prominent experts, in groups with a limited number of trainees. In all the courses the trainees have direct contact with the trainer, take part in discussions and can have answers on their questions. The Institute posts the PowerPoint presentations from all the implemented courses on the internet portal of the Agricultural Advisory Service to be available for the advisors from PSSS, agricultural producers and other interested subjects. Moreover, as the training courses are supported with educational materials in the form of flayers, manuals, brochures, leaflets and online applications on the PSSS portal (www.psss.rs). In the previous decades, the Institute for Science Application in Agriculture through its work on training courses and applied research has greatly contributed to the transfer of scientific achievements from all areas of agriculture, mainly to the Agricultural Advisory Service (PSSS) and agricultural producers. The expert team from the Institute consists of prominent experts in the most important areas of agriculture, who can use their knowledge to meet the demands of multidisciplinary projects from modern agriculture. We have made this catalogue to present part of the educational programmes we organise that can be useful for your future professional development.У циљу стицања и унапређења знања и вештина из области пољопривреде, Институт за примену науке у пољопривреди (ИПН), као Овлашћена организација од стране Министарства пољопривреде и заштите животне средине Републике Србије, од 2010. године, организује едукације саветодаваца Пoљопривредне саветодавне и стручне службе Републике Србије (ПССС). Континуирана едукација саветодаваца суштински доприноси трансферу најновијих знања до пољопривредних произвођача, а реализује се у циљу јачања конкурентности пољопривредне производње и повећања квалитета производа. Учесници едукација су и удружења призвођача, локалне самоуправе, центри за рурални развој, невладине организације и сви остали заинтересовани за стицање и унапређење знања. Полазницима едукација Институт издаје Сертификат о завршеној едукацији/тренингу из области саветодавних послова у пољопривреди, који је услов за стицање Лиценце за обављање саветодавних послова. Програм едукација израђује се на бази процене потреба саветодаваца и пољопривредних произвођача и приоритета пољопривреде и руралног развоја на нивоу Републике Србије. Програми едукација реализују се финансирањем од стране Министарства пољопривреде и заштите животне средине Републике Србије, као и кроз учешће партнерских организација (Институт за ратарство и повртарство из Новог Сада, GIZ, SDC), уз техничку помоћ USDA, и сарадњу на пројектима (TEMPUS, IPA, FADN). Институт организује 10 до 20 модула годишње. У периоду од 2010. do 2016. године реализовао је 54 модула и 3 радионице, као и 8 семинара Пољопривредне саветодавне и стручне службе Републике Србије. Све модуле одобрио је Стручни савет за саветодавство и примењена истраживања Министарства пољопривреде и заштите животне средине Републике Србије. Институт је са партнерима на TEMPUS пројекту (544072-TEMPUS-1-2013-1-RS-TEMPUSSMHES (2013 – 4604/001 - 001): Building Capacity of Serbian Agricultural Education to Link with Society (CaSA) - Изградња капацитета српског образовања у области пољопривреде ради повезивања са друштвом (CaSA)), током 2015. и 2016. године развио и реализовао 10 модула. Посебан допринос огледа се у развоју модула за учење на даљину (e-learning), који имају за циљ изградњу капацитета ПССС и капацитета пољопривредног образовања у Републици Србији кроз савремене видове учења. Едукације обухватају све области пољопривредне производње, као што су менаџмент производње, стандарди и регулативе ЕУ, сеоски туризам, рурални развој, мере аграрне политике и едукације за саветодавне технике и вештине саветодаваца. Задатак едукација је да омогуће: 1. Осавремењавање односно иновирање знања - из области нових и савремених технологија производње, 2. Проширење знања - из области које нису биле обухваћене редовним образовањем и 3. Стицање примењених знања - овладавање саветодавним вештинама. ИНСТИТУТ ЗА ПРИМЕНУ НАУКЕ Овлашћена организација за обуку пољопривредних саветодаваца и пољопривредних У циљу стицања и унапређења знања и вештина примену науке у пољопривреди (ИПН), као Министарства пољопривреде и заштите животне године, организује едукације саветодаваца Пoљопривредне Републике Србије (ПССС). Континуирана едукација саветодаваца суштински до пољопривредних произвођача, а реализује пољопривредне производње и повећања квалитета производа. Учесници едукација су и удружења призвођача, локалне развој, невладине организације и сви остали заинтересовани знања. Полазницима едукација Институт издаје Сертификат области саветодавних послова у пољопривреди, обављање саветодавних послова. Програм едукација израђује се на бази процене потреба произвођача и приоритета пољопривреде и руралног Програми едукација реализују се финансирањем од заштите животне средине Републике Србије, као и (Институт за ратарство и повртарство из Новог Сада, и сарадњу на пројектима (TEMPUS, IPA, FADN). Институт организује 10 до 20 модула годишње. реализовао је 54 модула и 3 радионице, као и 8 семинара стручне службе Републике Србије. Све модуле одобрио примењена истраживања Министарства пољопривреде Републике Србије. Институт је са партнерима на TEMPUS пројекту (544072-(2013 – 4604/001 - 001): Building Capacity with Society (CaSA) - Изградња капацитета српског ради повезивања са друштвом (CaSA)), током 2015. модула. Посебан допринос огледа се у развоју модула имају за циљ изградњу капацитета ПССС и капацитета Републици Србији кроз савремене видове учења. Едукације обухватају све области пољопривредне производње, стандарди и регулативе ЕУ, сеоски политике и едукације за саветодавне технике и вештине Задатак едукација је да омогуће: 1. Осавремењавање односно иновирање знања технологија производње, 2. Проширење знања - из области које нису биле обухваћене 3. Стицање примењених знања - овладавање саветодавним Едукације се реализују кроз различите методолошке типове обука: тематска предавања у учионици, практична обука, учење н а д аљину ( e-learning) и комбиновано тематска предавања и учење на даљину (blended). Ради осигурања квалитета и практичне применљивости Инстутут реализује едукације у сарадњи са реномираним стручњацима и у групама са ограниченим бројем учесника. Све наше едукације карактерише непосредан контакт учесника са предавачем, могућност дискусије и добијања одговора на конкретна питања. За све реализоване едукације, Институт поставља Power point презентације на порталу ПССС (www.psss.rs) које су доступне саветодавцима, пољопривредним произвођачима и осталим заинтересованим корисницима. Такође, као подршка едукацијама израђују се едукативни материјали у форми флајера, приручника, брошура, лифлета и on line апликација на порталу ПССС. Током протеклих деценија Институт је својим радом кроз едукације и примењена истраживања дао изузетан допринос трансферу научноистраживачких достигнућа из свих области пољопривреде, првенствено ка пољопривредним саветодавним и стручним службама Србије (ПССС) и пољопривредним произвођачима. Стручни тим Института чине реномирани стручњаци из најзначајнијих области пољопривреде, који својим знањем могу да одговоре захтевима мултидисциплинарних пројеката из домена савремене пољопривреде. Овај Каталог направили смо са жељом да вам представимо део едукативних програма које организујемо, а могу вам бити од значаја у даљем стручном и професионалном напредовању

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society

International audienceThis position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a Position Statement and new risk assessment tools from the Cardio‐Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio‐Oncology Society

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the C

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved