Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice

Chronic lung diseases are associated with persistent lung inflammation and damage. The mechanisms that govern the chronic nature of these disorders are not known. Adenosine is a signaling nucleoside that is generated in hypoxic environments such as that found in the inflamed lung, which suggests that it might serve a regulatory role in chronic lung diseases. Support for this hypothesis comes from studies in adenosine-deaminase-deficient mice where lung adenosine levels accumulate in association with increased lung inflammation and damage. Furthermore, lowering adenosine levels or antagonizing adenosine receptors can reverse pulmonary phenotypes in this model, suggesting that chronic adenosine elevations can affect signaling pathways that mediate aspects of chronic lung disease.     

Too much of a good thing: suicide prevention promotes chemoresistance in ovarian carcinoma

Ovarian cancer is the most lethal of gynecologic malignancies. Currently, standard treatment for epithelial ovarian cancer consists of surgical debulking followed by adjuvant chemotherapy with a platinum-based drug coupled with paclitaxel. While initial response to chemotherapy is high, the majority of patients develop recurrent disease which is characterized by chemoresistance. The primary cytotoxic effect of many chemotherapy drugs is mediated by apoptotic response in tumor cells. Recent data indicates that cross talk between the tumor microenvironment and malignant epithelial cells can influence apoptotic response as well. The identification of molecules involved in the regulation and execution of apoptosis, and their alterations in ovarian carcinoma have provided new insights into the mechanism behind the development of chemoresistance in this disease. Our challenge is now to devise strategies to circumvent cell death defects and ultimately improve response to treatment in ovarian carcinoma patients.     

Too little,too much or just right: Injury/illness sensitivity and intentions to drink as a basis for alcohol consumer segmentation

Background: Although alcohol is the most socially accepted drug, little is known about the classification of alcohol consumers into clusters influencing drinking outcomes. Past research has demonstrated that injury/illness sensitivity predicts health protecting behaviors. Objectives: The present study explored whether alcohol consumers can be classified based on injury/illness sensitivity and intentions to reduce drinking, and whether the identified clusters exhibited meaningful differences in negative affect and drinking levels. Methods: Four-hundred and eighty-six participants (54.3% male; mean [SD] age?=?26.5 [7.2] years) completed online questionnaires between July and October of 2017. Questions were asked pertaining to injury/illness sensitivity, intentions to reduce drinking, negative affect, and heavy drinking behavior. A k-means cluster analysis was performed on illness/injury sensitivity and intentions to reduce drinking scores. We then examined whether clusters varied according to negative affect or drinking variables. Results: The k-means cluster analysis identified four clusters: Insensitive non-internalizers, Insensitive internalizers, Sensitive non-internalizers, and Sensitive internalizers. Sensitive internalizers reported the highest, whereas Insensitive non-internalizers reported the lowest, negative affect. Sensitive internalizers also had the lowest percentage of heavy drinkers. Conclusion/importance: Current findings add to the alcohol literature by indicating that high sensitivity to illnesses/injuries and the internalization of sensitivities via behavior change intentions may provide the best protection against high alcohol consumption levels.     

Checkpoint-modulating immunotherapies in tumor treatment: Targets,drugs, and mechanisms

Tumor immunotherapy, as a new treatment of cancer, has been developing on the basis of tumor immunology. Tumor immunotherapy stimulates and enhances the function of immune system in human bodies, in order to control and kill tumor cells. It is often used as an adjuvant therapy combined with surgery, chemotherapy, radiotherapy and other conventional methods. Cancer immunotherapies involve cells, antibodies and cytokines, etc. Some immunotherapies are widely used to activate the immune system, while some others precisely target at different tumor antigens. With the development of tumor immunotherapy, immune regulation activities of small molecules and biological agents have been gradually becoming a hot research area these years. In this review, we summarize the therapeutic targets, drugs, biologics, and their mechanisms in tumor immunotherapies.     

FDA's conduct, review, and evaluation of inspections of clinical investigators.

This review of the Food and Drug Administration's Bioresearch Monitoring Program focuses on the inspection of clinical investigators who study investigational drugs. The differences between routine, "for-cause," and bioequivalency/bioavailability inspections are examined, with emphasis on the responsibilities of the clinical investigator, reasons for conducting the inspections, and problems found. Important aspects of the inspection report, such as protocol adherence, records maintenance, informed consent, institutional review board approval, and drug accountability, are outlined. The disqualification and consent agreement processes for investigators with serious problems are explained. FDA policies on third-party notification and remote data entry are noted.     

State sanctioned killing in the name of drugs: Laws,practice and conflicting trends in Asia

The last decade has seen a significant amount of progress in the struggle to abolish the death penalty for drug offences, a practice that is both illegal under international law and proven to be ineffective. Political, legal and policy developments at the international, regional and national level have led to a progressive shift away from capital punishment as a tool for drug control, resulting in a relatively sharp decrease in global executions. Yet a small number of countries, primarily in Asia, continue to aggressively pursue the policy, executing hundreds of disadvantaged individuals every year, often following trials that do not meet international standards of fairness. At the same time, populist rhetoric advocating for the death penalty for drugs is on the rise in the region, reinvigorating aggressive drug wars and threatening to undermine the framework of existing international legal obligations and unravel decades of progress.     

Apoptosis in the myocardium: much is still expected

Apoptosis continues to be a controversial concept and subject of debate among scientists regarding its value as the basis for new therapeutic strategies. Today, it is widely accepted that the death of cardiac myocytes under a variety of conditions appears to be apoptotic based on a variety of criteria. However, the significance of these observations and how the insights into apoptotic molecular pathways may provide novel therapeutic targets remains to be determined. It is important to reconsider the pertinent underlying mechanisms of apoptosis regulation, and how these molecular pathways may be viewed in the functioning, intact heart. This knowledge can be applied in pursuit of practical goals in a search for new ways to prevent myocardial damage following such injuries as ischaemia/reperfusion or exposure to cardiotoxic drugs. Although recent literature contains reports of positive findings, there has not yet been a rigorous application of the model of apoptosis in the myocardium, and the potential for development of new therapeutic strategies is not yet understood.     

Accuracy versus transparency in pharmacoeconomic modelling: finding the right balance

As modellers push to make their models more accurate, the ability of others to understand the models can decrease, causing the models to lose transparency. When this type of conflict between accuracy and transparency occurs, the question arises, "Where do we want to operate on that spectrum?" This paper argues that in such cases we should give absolute priority to accuracy: push for whatever degree of accuracy is needed to answer the question being asked, try to maximise transparency within that constraint, and find other ways to replace what we wanted to get from transparency. There are several reasons. The fundamental purpose of a model is to help us get the right answer to a question and, by any measure, the expected value of a model is proportional to its accuracy. Ironically, we use transparency as a way to judge accuracy. But transparency is not a very powerful or useful way to do this. It rarely enables us to actually replicate the model's results and, even if we could, replication would not tell us the model's accuracy. Transparency rarely provides even face validity; from the content expert's perspective, the simplifications that modellers have to make usually raise more questions than they answer. Transparency does enable modellers to alert users to weaknesses in their models, but that can be achieved simply by listing the model's limitations and does not get us any closer to real accuracy. Sensitivity analysis tests the importance of uncertainty about the variables in a model, but does not tell us about the variables that were omitted or the structure of the model. What people really want to know is whether a model actually works. Transparency by itself can't answer this; only demonstrations that the model accurately calculates or predicts real events can. Rigorous simulations of clinical trials are a good place to start. This is the type of empirical validation we need to provide if the potential of mathematical models in pharmacoeconomics is to be fully achieved.     

Adiponectin and Leptin: New Targets in Inflammation

Inflammation is a complex mechanism of cell/tissue responses to injuries triggered by multiple causes, including trauma, pathogens or autoimmune abnormal responses. In the last years, a novel line of thought is emerging by giving a more holistic vision of chronic arthropathies through a recently identified group of molecules, called adipokines. Actually, most of these recently identified factors, produced prevalently by white adipose tissue but also by cells of the joints (chondrocytes and synovial fibroblasts) and immune cells, play a significant role in chronic inflammation. Adipokines dysregulation has emerged as a common characteristic of chronic inflammation in rheumatic diseases in particular when obesity or, more precisely, adipose tissue dysfunction is associated with common rheumatic diseases, such as osteoarthritis and rheumatoid arthritis. In this MiniReview, we discuss the role of adipokines in osteoarthritis and rheumatoid arthritis providing an updated overview of their pathophysiological role and potential use as therapeutic targets.     

Price differentiation and transparency in the global pharmaceutical marketplace

Pharmaceutical manufacturers have increased the availability of their products and sometimes increased their own financial returns by charging lower prices outside of the US and by discounting to lower-income patients in the US. Examples include discounted HIV-AIDS drugs in developing countries and pharmaceutical manufacturers' discount cards in the US. Representatives of some international organisations argue that the price reductions are insufficient to make the medications widely available to lower-income patients.The WHO advocates both differential pricing and price transparency. While its efforts are well meaning, this paper identifies six concerns about its methods of comparing the price of a given molecule across manufacturers and across countries. More significantly, the WHO efforts to increase transparency are likely to lead to less price differentiation and less access to innovative pharmaceuticals. An important reason why manufacturers are reluctant to charge lower prices in lower-income countries is that they fear that such low prices will undermine the prices they charge to higher-income consumers. International organisations should not facilitate transparency but should dissuade governments from making price comparisons and basing their prices on those of lower-income countries. Furthermore, they should endeavour to keep low-priced and free drugs in the hands of the low-income consumers for which they were intended.