Emerging antibody-targeted therapy in leukemia and lymphoma: current concepts and clinical implications

The success of immune-mediated therapies has encouraged studies on passive and active immunotherapy in leukemia and lymphoma. This review outlines the impact of increasing insights from basic immunology studies on the potentiation of effective immune responses and the identification of new antigens as targets for antibody (Ab)-targeted therapies. The principles of treatment in leukemia and lymphoma based on current knowledge on the classification of hematologic malignancies are reviewed, and discussed in the context of a rationale to implement new Ab-targeted immunotherapeutic approaches. An update is provided on the use of Ab-targeted therapies in clinical trials with emphasis on new emerging strategies to further expand the successful field of immunotherapy in leukemia and lymphoma.     

Emerging concepts in disease management: a role for antimicrobial therapy in coronary artery disease

Coronary artery disease, the leading cause of morbidity and mortality in developed countries, is a chronic inflammatory process that develops in response to a variety of injuries. A number of microbial organisms have been implicated in its pathogenesis. The strongest evidence to date for an association between an infectious agent and coronary heart disease is that for Chlamydia pneumoniae. Evidence implicating other microbial organisms is much less compelling. Sero-epidemiological and pathological data have linked infection with C. pneumoniae to atherosclerotic coronary artery disease. A possible mechanism by which C. pneumoniae may participate in the pathogenesis of atherosclerosis is through immune activation and the initiation of a chronic inflammatory state in the infected arterial wall. Locally secreted inflammatory cytokines trigger a cascade of secondary cellular processes that lead to characteristic structural changes. C. pneumoniae has been detected in atherosclerotic plaques and in the serum of patients with coronary artery disease. It induces foam cells (the hallmark of early atherosclerosis) and it markedly accelerates this disease process in animal models. C. pneumoniae has been associated with elevated levels of inflammatory cytokines and acute phase reactants. Data from three interventional studies in humans have suggested that treatment with antibiotics decreases inflammatory markers and perhaps influences the anti-C. pneumoniae antibody titers; however, adverse clinical events were not uniformly reduced in all trials. Two large prospective clinical trials, the WIZARD trial and ACES, are underway to confirm these preliminary findings and test the hypothesis that antibiotics may be beneficial in preventing or modifying the course of coronary artery disease. At present, antimicrobial therapy for atherosclerosis is not advocated outside of well-controlled research settings.     

Emerging concepts in disease management: a role for antimicrobial therapy in coronary artery disease

Coronary artery disease, the leading cause of morbidity and mortality in developed countries, is a chronic inflammatory process that develops in response to a variety of injuries. A number of microbial organisms have been implicated in its pathogenesis. The strongest evidence to date for an association between an infectious agent and coronary heart disease is that for Chlamydia pneumoniae. Evidence implicating other microbial organisms is much less compelling. Sero-epidemiological and pathological data have linked infection with C. pneumoniae to atherosclerotic coronary artery disease. A possible mechanism by which C. pneumoniae may participate in the pathogenesis of atherosclerosis is through immune activation and the initiation of a chronic inflammatory state in the infected arterial wall. Locally secreted inflammatory cytokines trigger a cascade of secondary cellular processes that lead to characteristic structural changes. C. pneumoniae has been detected in atherosclerotic plaques and in the serum of patients with coronary artery disease. It induces foam cells (the hallmark of early atherosclerosis) and it markedly accelerates this disease process in animal models. C. pneumoniae has been associated with elevated levels of inflammatory cytokines and acute phase reactants. Data from three interventional studies in humans have suggested that treatment with antibiotics decreases inflammatory markers and perhaps influences the anti-C. pneumoniae antibody titers; however, adverse clinical events were not uniformly reduced in all trials. Two large prospective clinical trials, the WIZARD trial and ACES, are underway to confirm these preliminary findings and test the hypothesis that antibiotics may be beneficial in preventing or modifying the course of coronary artery disease. At present, antimicrobial therapy for atherosclerosis is not advocated outside of well-controlled research settings.     

Emerging concepts in osteoporosis and bone strength

OBJECTIVE: Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength and increased fracture risk. The factors that contribute to bone strength include bone mineral density (BMD) and bone quality, which encompasses factors such as bone turnover, microarchitecture, mineralization, and geometry. The objective of this paper was to review the factors that contribute to bone strength and osteoporosis. RESEARCH DESIGN: A MEDLINE search of English language journals between 1 January 1995 and 1 March 2005 was conducted using the term 'osteoporosis' combined with 'bone strength' or 'bone quality'. Reference lists of pivotal studies and reviews were also examined. Studies were otherwise not excluded on the basis of quality or size, the aim being to present an overview of research conducted to date on osteoporosis and bone strength. RESULTS: While there is a relationship between BMD and fracture risk, evidence suggests that BMD measurements reflect only 1 component of bone strength. For example, small changes in BMD produced by osteoporosis treatments do not fully explain the reductions in fracture risk observed after initiation of therapy, and substantial fracture risk reduction is observed before peak increases in BMD are achieved. In addition to their effects on BMD, anti-resorptive therapies for osteoporosis (i.e., bisphosphonates, selective estrogen receptor modulators, calcitonin, and estrogen) produce positive effects on bone turnover, microarchitecture, and/or mineralization, all of which can contribute to the reductions in fracture risk observed with these agents. Anabolic agents such as teriparatide also appear to have beneficial effects on bone strength independent of bone mass. New, non-invasive, high-resolution imaging methods, such as magnetic resonance imaging and computed tomography, may offer a comprehensive assessment of bone quality in the future. CONCLUSIONS: The development of clinical tools that assess bone quality independent of BMD will be essential to advance our assessment of fracture risk and response to osteoporosis treatment.     

Emerging concepts and approaches for chemokine-receptor drug discovery

Importance of the field: Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.

Areas covered in this review: Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.

What the reader will gain: Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.

Take home message: Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil^? for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.     

Emerging concepts on the use of ketamine for chronic pain

ABSTRACT

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.

Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine’s action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.

Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine’s analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine’s ability to modulate the affective-motivational dimension of pain.     

Emerging targets for COPD therapy

No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. However, several new treatments that target the inflammatory process are in clinical development. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include adhesion molecule and chemokine-directed therapy, as well as therapies to combat tumour necrosis factor-alpha and augment interleukin-10. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B4 receptor antagonists. Epidermal growth factor receptor kinase inhibitors and calcium-activated chloride channel inhibitors have potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed against transforming growth factor-beta1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.     

Recent approaches to periodontal therapy

Periodontal diseases encompass a variety of disease classifications, all involving inflammation of the supporting tissues of the teeth. When progressive, these diseases ultimately lead to the destruction of attachment apparatus including bone and periodontal ligament, culminating in eventual tooth loss. Inflammation extends from superficial gingival structures, effecting adjacent submerged bone and periodontal ligament. Progression modifies an initially highly favourable, reversible diagnosis of gingivitis to a less favourable, somewhat irreversible situation: periodontitis. Periodontal diseases manifest variable and sometimes unpredictable prognoses, are generally somewhat complicated and costly to treat and often require long-term follow-up for maintenance and monitoring. Treatment aims at restoration of health and control of future disease within a functional, albeit reduced, periodontium. In the strictest sense, periodontal diseases are not 'cured'. The conventional, usually successful, approach to the treatment of patients with gingivitis or chronic periodontitis has involved non-surgical mechanical periodontal therapy [1,2]. Some patients manifest localised or generalised continuous attachment loss and periodontal destruction. These sites are prime candidates for alternative therapeutic regimens. This review highlights some of the recent advances in periodontal therapy and evokes some questions that should be addressed during future studies.     

Recent approaches to periodontal therapy

Periodontal diseases encompass a variety of disease classifications, all involving inflammation of the supporting tissues of the teeth. When progressive, these diseases ultimately lead to the destruction of attachment apparatus including bone and periodontal ligament, culminating in eventual tooth loss. Inflammation extends from superficial gingival structures, effecting adjacent submerged bone and periodontal ligament. Progression modifies an initially highly favourable, reversible diagnosis of gingivitis to a less favourable, somewhat irreversible situation: periodontitis. Periodontal diseases manifest variable and sometimes unpredictable prognoses, are generally somewhat complicated and costly to treat and often require long-term follow-up for maintenance and monitoring. Treatment aims at restoration of health and control of future disease within a functional, albeit reduced, periodontium. In the strictest sense, periodontal diseases are not ‘cured’. The conventional, usually successful, approach to the treatment of patients with gingivitis or chronic periodontitis has involved non-surgical mechanical periodontal therapy [1,2]. Some patients manifest localised or generalised continuous attachment loss and periodontal destruction. These sites are prime candidates for alternative therapeutic regimens. This review highlights some of the recent advances in periodontal therapy and evokes some questions that should be addressed during future studies.     

Current concepts in rational therapy for haemochromatosis.

Genetic haemochromatosis is characterised by an inappropriately high rate of iron absorption by the small intestine. The disease is transmitted as an autosomal recessive condition. The gene frequency in the Caucasian population is approximately 1 in 20 and the disease frequency is 1 in 400. Excessive iron deposition occurs in the liver, pancreas, heart, pituitary and joints and hepatic iron concentrations above approximately 400 mumol/g dry weight are always associated with fibrosis and usually with cirrhosis and progressive liver failure. Accurate diagnosis depends upon the demonstration of elevated hepatic iron stores. An hepatic iron index [hepatic iron concentration (in mumol/g dry weight) divided by patient age] of greater than 2.0 distinguishes homozygous subjects from the other conditions in which slight increases in hepatic iron concentration may occur, e.g. in a subject heterozygous for haemochromatosis or alcoholic liver disease. If cirrhosis is present, patients are at a high risk of developing hepatocellular carcinoma. Therefore, they should undergo regular abdominal ultrasound and alpha-fetoprotein estimation. In the absence of cirrhosis, phlebotomy restores life expectancy to normal. Venesection should be continued until all excess iron stores are removed as judged by failure of a rise in haemoglobin concentration on cessation of phlebotomy. Screening of first degree relatives should commence from a young age (e.g. 10 years). If serum ferritin or transferrin saturation are abnormal, liver biopsy should be undertaken. HLA typing of the family allows for the identification of those siblings who are most likely to develop the disease. Secondary iron overload is often multifactorial in origin. Iron chelation therapy with subcutaneous deferoxamine (desferrioxamine) should only commence after careful consideration of the potential benefits in each individual patient.     

Emerging roles of Aurora-A kinase in cancer therapy resistance

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.