Science translational medicine
-
Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. ⋯ Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.
-
Therapeutic off-target activities are well recognized for small-molecule drugs. In contrast, monoclonal antibodies (mAbs) traditionally are believed to act specifically and lack off-target therapeutic effects. In this issue of Science Translational Medicine, Fornoni et al. show therapeutic benefit, through an off-target-mediated mechanism, of the mAb drug rituximab in recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation. These data shed new light on FSGS pathogenesis and suggest new therapeutic interventions for proteinuric diseases.
-
Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid-related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. ⋯ Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection.
-
Today, modern technologies in genomics, biomarker detection, and molecular imaging are providing information that will enable physicians to select appropriate treatments for individual cancer patients from among more than 800 new experimental drugs and antibodies that target the products of the aberrant genes that can cause cancer. At this promising time in cancer research, the U. S. ⋯ Multiple stakeholders in the academic, governmental, and commercial sectors must better integrate their efforts. Improvements must be made in the incorporation of new technologies, prioritization, and timely completion of trials, and provision of financial support that covers actual costs. The result will be more rapid translation of recent scientific advances into increased benefits for patients with cancer.
-
Clinical Trial
The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.
Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). ⋯ The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.