Biofutur最新文献

Chronic Obstructive Pulmonary Disease (COPD) affects 12-16 million people in the United States and is the third-leading cause of death. In developed countries, smoking is the greatest risk factor for the development of COPD, but other exposures also contribute to the development and progression of the disease. Several studies suggest, though are not definitive, that outdoor air pollution exposure is linked to the prevalence and incidence of COPD. Among individuals with COPD, outdoor air pollutants are associated with loss of lung function and increased respiratory symptoms. In addition, outdoor air pollutants are also associated with COPD exacerbations and mortality. There is much less evidence for the impact of indoor air on COPD, especially in developed countries in residences without biomass exposure. The limited existing data suggests that indoor particulate matter and nitrogen dioxide concentrations are linked to increased respiratory symptoms among patients with COPD. In addition, with the projected increases in temperature and extreme weather events in the context of climate change there has been increased attention to the effects of heat exposure. Extremes of temperature-both heat and cold-have been associated with increased respiratory morbidity in COPD. Some studies also suggest that temperature may modify the effect of pollution exposure and though results are not conclusive, understanding factors that may modify susceptibility to air pollution in patients with COPD is of utmost importance.

We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1) and killer cell immunoglobulin-like receptors (KIR2DL1/2/3) were expressed at low level in most cultures. Without blockade, myeloid leukaemia cells were susceptible to autologous and allogeneic CIK-mediated cytotoxicity. Blockade of KIR, LAG-3, PD-1 and TIM-3 but not CTLA-4 resulted in remarkable increase in killing against these targets, even in those with poor baseline cytotoxicity. ALL and MM targets were resistant to CIK-mediated cytotoxicity, and blockade of receptors did not increase cytotoxicity to a meaningful extent. Combination of inhibitors against two receptors did not further increase cytotoxicity. Interestingly, potentiation of CIK killing by blocking antibodies was not predicted by expression of receptors on CIK and their respective ligands on the targets. Compared to un-activated T and NK cells, blockade potentiated the cytotoxicity of CIK cells to a greater degree and at a lower E:T ratio, but without significant increase in cytotoxicity against normal white cell. Our findings provide the basis for clinical trial combining autologous CIK cells with checkpoint inhibitors for patients with AML.

High-quality evaluations of both efficacy and safety are essential to characterize the risk-benefit profile of antibiotics. The current US Food and Drug Administration guidelines on trial design for community-acquired pneumonia have several weaknesses, including the failure to insist on the use of double blinding and intention-to-treat analysis. A primary difficulty with noninferiority designs is that poorly conducted studies, which increase noise, are biased toward the conclusion of noninferiority even in the presence of important differences between the test drug and the control drug. Additionally, results of noninferiority trials, in the absence of a well-established anchor, may be difficult to interpret. The US Food and Drug Administration drug-evaluation process includes preclinical studies to assess toxicity and a series of clinical studies involving humans to define efficacy and to identify potential safety problems. When signals are apparent, as they were for telithromycin (liver toxicity in rats, dogs, and monkeys) or for sparfloxacin (prolongation of the QT interval in dogs), it is nonetheless essential that these signals are fully and fairly evaluated in human studies with adequate power. Risks of antibiotic use, such as prolongation of the corrected QT interval and sudden death, may be acceptable in the presence of convincing benefits for patients with severe, life-threatening infections; however, the risk-benefit profile derived from severe infections cannot necessarily be generalized to mild or self-limited infections, for which the same serious drug-associated risks are likely to exceed the benefits. Complete and proper evaluation of both safety and efficacy in specific situations is essential to define the risk-benefit profiles of all drugs, including antibiotics.