Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer

IntroductionSeveral anaplastic lymphoma kinase (ALK)-inhibitors (ALKi) have been approved for the treatment of ALK-translocated advanced or metastatic Non Small Cell Lung Cancer (NSCLC), amongst crizotinib and alectinib. This forces physicians to choose the most suitable compound for each individual patient on the basis of the tumor´s genetic profile, but also in regard to toxicities and potential co-treatments. Moreover, targeted therapies might be combined with or followed by immunotherapy, which underlines the importance to gain detailed knowledge about potential immunomodulatory effects of these inhibitors. We here aimed to 1.) determine whether ALKi display an immunosuppressive effect on human dendritic cells (DCs) as important mediators of antigen-specific immunity and to 2.) dissect whether this immunosuppression differs among ALKi.MethodsWe investigated the effect of alectinib and crizotinib on human monocyte-derived DCs (moDC) as most powerful antigen-presenting cells. We performed immunophenotyping by flow cytometry, migration, antigen uptake and cytokine assays.ResultsCrizotinib-treated DCs showed reduced activation markers, such as CD83, decreased chemokine-guided migration, lower antigen uptake and produced inferior levels of pro-inflammatory cytokines, especially Interleukin-12. In contrast, the immunosuppressive potential of alectinib was significantly less pronounced. This indicates that crizotinib might profoundly dampen anti-tumor immunity, while alectinib had no unfavourable immunosuppressive effects.ConclusionsOur results implicate that current ALKi differ in their capacity to suppress the activation, migration and cytokine production of DCs as essential mediators of T cell immunity. We show that crizotinib, but not alectinib, had immunosuppressive effects on DCs phenotype and reduced DC function, thereby potentially impairing anti-tumor immunity

Ewing sarcoma of the proximal phalanx of the little finger : Case report

El sarcoma de Ewing se presenta en la segunda década de la vida y tiene predilección por las diáfisis de los huesos largos y en la pelvis. Pueden existir localizaciones raras como en los en los metacarpianos. Reportamos un caso de sarcoma de Ewing localizado en la falange proximal del 5to dedo de la mano izquierda en un paciente masculino de 44 anos ˜ de edad. Ante la poca frecuencia de presentación, resulta importante considerar los diagnósticos diferenciales de otras patologías neoplásicas de la mano, como el osteosarcoma de células pequenas. ˜ Ésta es una rara pero agresiva forma de osteosarcoma cuyo diagnóstico es difícil de realizar y fue nuestra primera sospecha diagnóstica por valoración radiológica. Sin embargo, se caracterizó al sarcoma de Ewing con la ayuda de la biopsia y la histopatología. El control local de la enfermedad se logró mediante la excéresis del tumor con márgenes amplios.Reporte de caso137-142Paciente masculinoEwing’s sarcoma occurs in the second decade of life and has a predilection for thediaphysis of long bones and pelvis. There may be rare locations, such as in the metacarpals.A case is reported of Ewing’s sarcoma located in the proximal phalanx of the 5th finger of theleft hand in a male patient aged 44. Given the infrequency of presentation, it is importantto consider the differential diagnosis of other neoplastic diseases of the hand and small cellosteosarcoma. The latter is a rare but aggressive form of osteosarcoma, which is difficult to diagnose and was our first suspicion diagnosed by radiological assessment. However Ewing’ssarcoma was characterized with the help of the biopsy and histopathology. Local disease controlwas achieved by tumoral exeresis with wide margins

Mechanisms of receptor/coreceptor-mediated entry of enveloped viruses

Enveloped viruses enter host cells either through endocytosis, or by direct fusion of the viral membrane envelope and the membrane of the host cell. However, some viruses, such as HIV-1, HSV-1, and Epstein-Barr can enter a cell through either mechanism, with the choice of pathway often a function of the ambient physical chemical conditions, such as temperature and pH. We develop a stochastic model that describes the entry process at the level of binding of viral glycoprotein spikes to cell membrane receptors and coreceptors. In our model, receptors attach the cell membrane to the viral membrane, while subsequent binding of coreceptors enables fusion. The model quantifies the competition between fusion and endocytotic entry pathways. Relative probabilities for each pathway are computed numerically, as well as analytically in the high viral spike density limit. We delineate parameter regimes in which fusion or endocytosis is dominant. These parameters are related to measurable and potentially controllable quantities such as membrane bending rigidity and receptor, coreceptor, and viral spike densities. Experimental implications of our mechanistic hypotheses are proposed and discussed.Comment: 10 Figure

Novel Approaches to Inhibit HIV Entry

Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor—either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification of genetic polymorphisms, such as the 32 base-pair deletion in the ccr5 gene (ccr5∆32) that confers resistance to infection in homozygous individuals, and has also resulted in the development of entry inhibitors—small molecule antagonists that block infection at the entry step. The recent demonstration of long-term control of HIV infection in a leukemic patient following a hematopoietic stem cell transplant using cells from a ccr5∆32 homozygous donor highlights the important role of the HIV entry in maintaining an established infection and has led to a number of attempts to treat HIV infection by genetically modifying the ccr5 gene. In this review, we describe the HIV entry process and provide an overview of the different classes of approved HIV entry inhibitors while highlighting novel genetic strategies aimed at blocking HIV infection at the level of entry

Mechanisms of viral entry: sneaking in the front door

Recent developments in methods to study virus internalisation are providing clearer insights into mechanisms used by viruses to enter host cells. The use of dominant negative constructs, specific inhibitory drugs and RNAi to selectively prevent entry through particular pathways has provided evidence for the clathrin-mediated entry of hepatitis C virus (HCV) as well as the caveolar entry of Simian Virus 40. Moreover, the ability to image and track fluorescent-labelled virus particles in real-time has begun to challenge the classical plasma membrane entry mechanisms described for poliovirus and human immunodeficiency virus. This review will cover both well-documented entry mechanisms as well as more recent discoveries in the entry pathways of enveloped and non-enveloped viruses. This will include viruses which enter the cytosol directly at the plasma membrane and those which enter via endocytosis and traversal of internal membrane barrier(s). Recent developments in imaging and inhibition of entry pathways have provided insights into the ill-defined entry mechanism of HCV, bringing it to the forefront of viral entry research. Finally, as high-affinity receptors often define viral internalisation pathways, and tropism in vivo, host membrane proteins to which viral particles specifically bind will be discussed throughout

Deciphering the pathogenesis of tendinopathy: a three-stages process

Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments

Medium-energy shock wave therapy in the treatment of rotator cuff calcifying tendinitis

To evaluate the results of the treatment with medium-energy extracorporeal shock wave therapy (ESWT) in rotator cuff calcifying tendinitis. Fifty-four non-consecutive patients, who were referred to our institute for rotator cuff calcifying tendinitis, were managed with a standardized protocol in four sessions of medium-energy (0.11 mJ/mm2) ESWT administered with an electromagnetic lithotriptor. Pain was evaluated at the end of each session, functional state of shoulder was assessed at 1 and 6 months after the end of procedure. All patients underwent radiographs and sonography imaging. No systemic or local complications. Thirty-eight patients (70%) reported satisfactory functional results. Radiographs and sonographs showed a disappearance of calcium deposit in 29 patients (54%) and in 19 patients (35%) it appeared to be reduced more than a half. A correlation was found between residual calcium deposit and the clinical outcome, but some patients showed a reduced pain without modification of calcium deposit. These results were unmodified at 6 months follow-up. Our protocol of medium-energy ESWT provides good results overall about pain modulation