Fifteen Years of Irinotecan Therapy for Pediatric Sarcoma: Where to Next?

Over the past 15 years, irinotecan has emerged as an important agent for treating pediatric sarcoma patients. This review summarizes the activity noted in previous studies, and outlines current issues regarding scheduling, route of administration, and amelioration of side effects. Also discussed are new pegylated and nanoliposomal formulations of irinotecan and its active metabolite, SN-38, as well as future plans for how irinotecan may be used in combination with other conventional cytotoxic as well as targeted agents

Profile of Veliparib and Its Potential in the Treatment of Solid Tumors

Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small-molecule inhibitors of PARP appear most effective when used to treat tumors with underlying defects in DNA repair, or when combined with DNA-damaging agents. Veliparib is one of several recently developed oral inhibitors of PARP currently in clinical trials. This review summarizes the pharmacology, mechanisms of action, toxicity, and activity of veliparib seen in clinical trials to date. Also discussed are proposed mechanisms of resistance, potential biomarkers of activity, and issues regarding patient selection and combination therapies that may optimize use of this exciting new agent

Targeting the PD-1 Pathway in Pediatric Solid Tumors and Brain Tumors

While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study

Assessment of Minimal Residual Disease in Ewing Sarcoma

Advances in molecular pathology now allow for identification of rare tumor cells in cancer patients. Identification of this minimal residual disease is particularly relevant for Ewing sarcoma, given the potential for recurrence even after complete remission is achieved. Using RT-PCR to detect specific tumor-associated fusion transcripts, otherwise occult tumor cells are found in blood or bone marrow in 20–30% of Ewing sarcoma patients, and their presence is associated with inferior outcomes. Although RT-PCR has excellent sensitivity and specificity for identifying tumor cells, technical challenges may limit its widespread applicability. The use of flow cytometry to identify tumor-specific antigens is a recently described method that may circumvent these difficulties. In this manuscript, we compare the advantages and drawbacks of these approaches, present data on a third method using fluorescent in situ hybridization, and discuss issues affecting the further development of these strategies

Correction : Cross-sectional focusing of red blood cells in a constricted microfluidic channel

Correction for ‘Cross-sectional focusing of red blood cells in a constricted microfluidic channel’ by Asena Abay et al., Soft Matter, 2020, 16, 534–543

Cross-sectional focusing of red blood cells in a constricted microfluidic channel

Constrictions in blood vessels and microfluidic devices can dramatically change the spatial distribution of passing cells or particles and are commonly used in biomedical cell sorting applications. However, the three-dimensional nature of cell focusing in the channel cross-section remains poorly investigated. Here, we explore the cross-sectional distribution of living and rigid red blood cells passing a constricted microfluidic channel by tracking individual cells in multiple layers across the channel depth and across the channel width. While cells are homogeneously distributed in the channel cross-section pre-contraction, we observe a strong geometry-induced focusing towards the four channel faces post-contraction. The magnitude of this cross-sectional focusing effect increases with increasing Reynolds number for both living and rigid red blood cells. We discuss how this non-uniform cell distribution downstream of the contraction results in an apparent double-peaked velocity profile in particle image velocimetry analysis and show that trapping of red blood cells in the recirculation zones of the abrupt construction depends on cell deformability.Comment: accepted for soft matte

Structural investigation and strain analysis of a polyphase flower structure in the Lower Saxony Basin, Germany

The Lower Saxony Basin (LSB) is a part of the post-Variscan Central European Basin System. We used a 3-D reflection seismic dataset in the northern LSB, provided by RWE-DEA AG, Hamburg (c.f. Lohr et al. submitted) for our investigation, which is concerned with the detailed structural and kinematic analysis of a flower structure within Mesozoic strata. This data is used in turn to determine input parameters for further 3-D geometrical retro-deformation. The retro-deformation verifies our assumptions about the structure and tectonic processes, and gives further information about sub-seismic strain distribution with respect to the branch faults of the flower structure.conferenc

Expression of enzymatically inactive wasp venom phospholipase A1 in Pichia pastoris

Wasp venom allergy is the most common insect venom allergy in Europe. It is manifested by large local reaction or anaphylactic shock occurring after a wasp sting. The allergy can be treated by specific immunotherapy with whole venom extracts. Wasp venom is difficult and costly to obtain and is a subject to composition variation, therefore it can be advantageous to substitute it with a cocktail of recombinant allergens. One of the major venom allergens is phospholipase A1, which so far has been expressed in Escherichia coli and in insect cells. Our aim was to produce the protein in secreted form in yeast Pichia pastoris, which can give high yields of correctly folded protein on defined minimal medium and secretes relatively few native proteins simplifying purification. Residual amounts of enzymatically active phospholipase A1 could be expressed, but the venom protein had a deleterious effect on growth of the yeast cells. To overcome the problem we introduced three different point mutations at the critical points of the active site, where serine137, aspartate165 or histidine229 were replaced by alanine (S137A, D165A and H229A). All the three mutated forms could be expressed in P. pastoris. The H229A mutant did not have any detectable phospholipase A1 activity and was secreted up to the level of 4 mg/L in shake flask culture. It was purified by nickel‐affinity chromatography and its identity was confirmed by MALDI‐TOF mass spectrometry. The protein could bind IgE antibodies from wasp venom allergic patients and could inhibit the binding of wasp venom to IgE antibodies specific for phospholipase A1 as shown by Enzyme Allergo‐Sorbent Test (EAST). Moreover, the recombinant protein was allergenic in a biological assay as demonstrated by its capability to induce histamine release of wasp venom‐sensitive basophils. The recombinant phospholipase A1 presents a good candidate for wasp venom immunotherapy

Using Long-Duration Static Stretch Training to Counteract Strength and Flexibility Deficits in Moderately Trained Participants

Many sports injuries result in surgery and prolonged periods of immobilization, which may lead to significant atrophy accompanied by loss of maximal strength and range of motion and, therefore, a weak-leg/strong-leg ratio (as an imbalance index ∆ ) lower than 1. Consequently, there are common rehabilitation programs that aim to enhance maximal strength, muscle thickness and flexibility; however, the literature demonstrates existing strength imbalances after weeks of rehabilitation. Since no study has previously been conducted to investigate the effects of long-duration static stretch training to treat muscular imbalances, the present research aims to determine the possibility of counteracting imbalances in maximal strength and range of motion. Thirty-nine athletic participants with significant calf muscle imbalances in maximal strength and range of motion were divided into an intervention group (one-hour daily plantar flexors static stretching of the weaker leg for six weeks) and a control group to evaluate the effects on maximal strength and range of motion with extended and bent knee joint. Results show significant increases in maximal strength (d = 0.84–1.61, p < 0.001–0.005) and range of motion (d = 0.92–1.49, p < 0.001–0.002) following six weeks of static stretching. Group * time effects ( p < 0.001–0.004, η² = 0.22–0.55) revealed ∆ changes in the intervention group from 0.87 to 1.03 for maximal strength and from 0.92 to 1.11 in range of motion. The results provide evidence for the use of six weeks of daily, one hour stretching to counteract muscular imbalances. Related research in clinical settings after surgery is suggested

Die Proteste in Frankreich 2005: interdisziplinäre Perspektiven der Konfliktforschung

"Die Proteste in den französischen Vorstädten im Oktober/ November 2005 kamen für viele in Art, Ausmaß und Intensität überraschend. Bei genauerem Hinsehen zeigt sich jedoch, dass sich in den großen Städten Frankreichs schon seit geraumer Zeit in den sog. banlieues eine hochexplosive Mischung sozialer Probleme zusammenbraut, für die es nur noch geeigneter Anlässe bedarf, damit diese gewaltsam eskalieren. Im vorliegenden working paper soll aus verschiedenen disziplinären Perspektiven (Politikwissenschaft, Soziologie, Sozialpsychologie) auf die Proteste geschaut und ihre wichtigsten Aspekte analysiert werden. Peter Imbusch wirft einführend einige der mit den Protesten immer wieder auftauchenden Fragen auf, deren Beantwortung Gegenstand der nachfolgenden Beiträge ist. Johannes M. Becker benennt die Faktoren, die Ausbruch und Verlauf der Proteste bestimmt haben. Lars Schmitt verdeutlicht sodann die Bedingungen der Möglichkeit für das Entstehen einer Protestbewegung und stellt die Formierung einer solchen Bewegung als einen äußerst voraussetzungsreichen Prozess dar. Ulrich Wagner und Jost Stellmacher loten schließlich die mikrosoziologischen und sozialpsychologischen Aspekte aus, die Protestbewegungen Identität und Zusammenhalt bescheren und damit erst zielgerichtetes Handeln als Gruppe ermöglichen - oder eben auch nicht ermöglichen. Abschließend resümiert Peter Imbusch die Debatten mit einer konfliktsoziologischen Einbettung v.a. im Hinblick auf die Ursachen der Proteste und die Möglichkeiten eines Übergreifens auf Deutschland." (Autorenreferat). Inhaltsverzeichnis: Peter Imbusch: Die Proteste in Frankreich - einige einleitende Überlegungen (8-10); Johannes M. Becker: Frankreichs Vorstädte brennen wieder - eine Analyse in acht Schritten (11-16); Lars Schmitt: Wie ausgeschlossen muss man sein um zu protestieren? Sozialer Protest und seine Voraussetzungen (17-21); Ulrich Wagner, Jost Stellmacher: Makroprobleme und konkretes Verhalten oder: Wie kommt die Krise des Sozialstaats in den Molotowcocktail? (22-24); Peter Imbusch: Französische Zustände Verstehen - ein Resümee der Proteste (25-27)."The violent protests in the French suburbs in October/ November 2005 surprised many observers in their form, magnitude and intensity. On closer examination, however, it becomes obvious that an explosive mixture of social problems had been accumulating in the so-called banlieues of France's big cities for a fairly long time - circumstances under which violent escalations only require the adequate occasions. The working paper examines the protests in France from different disciplinary perspectives (political science, sociology, social psychology) and analyzes their central aspects. In the introduction, Peter Imbusch raises some of the recurring issues regarding the protests, which are being dealt with in more detail in the subsequent contributions. Johannes M. Becker specifies the factors which determined the outbreak and course of the protests. Lars Schmitt thereafter clarifies the conditions allowing for the emergence of a protest movement. He characterizes the development of such a movement as a process in which many preconditions must be fulfilled. Ulrich Wagner and Jost Stellmacher then fathom the micro-sociological and social-psychological aspects which only by bestowing protest movements with identity and cohesion allow for goal-oriented behavior as a group. In the conclusion, Peter Imbusch summarizes the different arguments in a conflict sociological perspective in view of the causes underlying the protests as well as the potentialities of an encroachment on Germany." (author's abstract