PD-1 as a potential target in cancer therapy

Recently, an improved understanding of the molecular mechanisms governing the host response to tumors has led to the identification of checkpoint signaling pathways involved in limiting the anticancer immune response. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway, normally involved in promoting tolerance and preventing tissue damage in settings of chronic inflammation. Many human solid tumors express PD ligand 1 (PD-L1), and this is often associated with a worse prognosis. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and have impaired antitumor functionality. Proof-of-concept has come from several preclinical studies in which blockade of PD-1 or PD-L1 enhanced T-cell function and tumor cell lysis. Three monoclonal antibodies against PD-1, and one against PD-L1, have reported phase 1 data. All four agents have shown encouraging preliminary activity, and those that have been evaluated in larger patient populations appear to have encouraging safety profiles. Additional data are eagerly awaited. This review summarizes emerging clinical data and potential of PD-1 pathway–targeted antibodies in development. If subsequent investigations confirm the initial results, it is conceivable that agents blocking the PD-1/PD-L1 pathway will prove valuable additions to the growing armamentarium of targeted immunotherapeutic agents. Next-generation immunotherapy agents that target the PD-1 checkpoint pathway are demonstrating antitumor activity and encouraging safety profiles in early clinical trials. Current and future clinical trials will provide new insights, and the evaluation of biomarkers and rational combination therapies is ongoing

NOD-like receptors and inflammation

The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1β production and translocation of nuclear factor-κB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function

Large falcine meningioma fed by callosomarginal branch successfully removed following contralateral interhemispheric approach

We report the case of a highly vascular facline meningioma removed following surgical ligation of a large callosomarginal feeding branch via a contralateral interhemispheric approach. Successfully addressing this vessel via a contralateral interhemispheric approach prior to any debulking allowed for en bloc Simpson Grade 1 tumor removal with minimal blood loss and short term tumor control without evidence of recurrence at 2 year follow up. A 56 year old man presented with first time generalized tonic-clonic seizure. Imaging revealed a right sided 5 cm falcine meningioma. The patient underwent pre-operative embolization of feeding branches, however, the most significant supply, arising from the right callosomarginal artery, could not be occluded. A bipartite frontotemporal craniotomy was performed. From a left sided interhemispheric approach the pericallosal and callosomarginal arteries were identified and the large callosomarginal tumor feeding branch were occluded using a straight Yasargil aneurysm clip. From the right the superior sagital sinus was ligated anteriorly and posteriorly. The sinus, falx, and adherent tumor were then removed en bloc. We present the case of a highly vascular falcine meningioma with a large callosomarginal feeding branch which was successfully occluded using surgical clipping of this vessel via a contralateral interhemispheric approach. This case provides an excellent example of one approach to directly dealing with large, deep interhemispheric feeding vessels unsuitable for embolization. A 3D animation of the surgical approach is provided for instructional purposes

Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS)

Cryopyrin-associated periodic syndromes (CAPS) are a subgroup of the hereditary periodic fever syndromes, which are rare autoinflammatory and inherited disorders, characterized by recurrent inflammation and varying degrees of severity. CAPS are thought to be driven by excessive production of interleukin-1β (IL-1β), through over-activation of the inflammasome by gain of function mutations in the gene encoding cryopyrin (NLRP3). This conclusion is supported by the remarkable efficacy of IL-1β blockade in these conditions. Rilonacept (ArcalystTM; Regeneron) is the first us Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle–Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade. Rilonacept has been associated with a decrease in disease activity, high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) in the treatment of CAPS. The clinical safety and efficacy of rilonacept in CAPS and non-CAPS populations will be summarized in this review. Rilonacept is also beneficial for patients who tolerate injections poorly, due to an extended half-life over the unapproved CAPS treatment, anakinra, requiring weekly rather than daily self-administration. Other autoinflammatory disorders may also benefit from rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever

Clinical challenges in the management of osteoporosis

While knowledge regarding the diagnosis and treatment of osteoporosis has expanded dramatically over the last few years, gaps in knowledge still exist with guidance lacking on the appropriate management of several common clinical scenarios. This article uses fictional clinical scenarios to help answer three challenging questions commonly encountered in clinical practice. The first clinical challenge is when to initiate drug therapy in a patient with low bone density. It is estimated that 34 million America have low bone density and are at a higher risk for low trauma fractures. Limitations of using bone mineral density alone for drug therapy decisions, absolute risk assessment and evidence for the cost-effectiveness of therapy in this population are presented. The second clinical challenge is the prevention and treatment of vitamin D deficiency. Appropriate definitions for vitamin D insufficiency and deficiency, the populations at risk for low vitamin, potential consequences of low vitamin D, and how to manage a patient with low vitamin D are reviewed. The third clinical challenge is how to manage a patient receiving drug therapy for osteoporosis who has been deemed a potential treatment failure. How to define treatment failure, common causes of treatment failure, and the approach to the management of a patient who is not responding to appropriate osteoporosis therapy are discussed

The role of the NLRP3 inflammasome in gout

Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1β, underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU ‘danger signal’. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1β antibody), and anakinra have all demonstrated treatment efficacy in such patients

Periodic fever syndrome and autoinflammatory diseases

The concept of autoinflammatory disease as a new disease classification has resulted in a paradigm shift in our understanding of the the broad spectrum of immunological diseases. The effectiveness of interleukin-1 blockade in a variety of disorders has resulted in a marked reduction in suffering for many of these patients

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

Inflammation causes debilitating human conditions and older treatments rely on global immunosuppression that non‐specifically alleviates symptoms. Currently, several monoclonal antibodies (mAbs) are available that specifically block pro‐inflammatory cytokines. These include mAbs specific to tumour necrosis factor (TNF), interleukin (IL)‐1β, IL‐6, IL‐17 and IL‐12/IL‐23. The chapter summarises the key elements in human inflammatory disease conditions, including various forms of arthritis, psoriasis, Crohn\u27s disease and ulcerative colitis, plus pyrin‐associated inflammatory syndromes and periodic fevers, to explain the benefit of cytokine neutralisation through mAb‐type reagents. The chapter reviews the efficacy and safety of the current repertoire of anti‐cytokine/cytokine receptor mAbs. It also discusses the known side effects and adverse events that are sometimes associated with systemic blockade of cytokines in vivo, and concludes that the accumulating knowledge of treatment failures can reveal unappreciated aspects of cytokine biology and even new treatment opportunities. The chapter includes mention of the rapidly expanding cohort of biosimilar mAbs and the mAbs to IL‐4, IL‐5 and IL‐13 that are now emerging, in addition to the need for treatments for disorders that remain refractory to the current repertoire of anti‐cytokine mAbs and conventional treatments. Thus, here we summarise the current status of anti‐cytokine mAbs for human inflammatory diseases

Investigating Student Understanding of Quantum Mechanics: Spontaneous Models of Conductivity

Students are taught several models of conductivity, both at the introductory and the advanced level. From early macroscopic models of current flow in circuits, through the discussion of microscopic particle descriptions of electrons flowing in an atomic lattice, to the development of microscopic non-localized band diagram descriptions in advanced physics courses, they need to be able to distinguish between commonly used, though sometimes contradictory, physical models. In investigations of student reasoning about models of conduction, we find that students often are unable to account for the existence of free electrons in a conductor and create models that lead to incorrect predictions and responses contradictory to expert descriptions of the physics. We have used these findings as a guide to creating curriculum materials that we show can be effective helping students to apply the different conduction models more effectively.Comment: 12 pages, 9 figures, 36 references and note