The 2018 Nobel Prize in Physiology or Medicine was awarded to pioneers in the field of cancer immunotherapy, as the utility of leveraging a patient's coordinated and adaptive immune system to fight ...the patient's unique tumour has now been validated robustly in the clinic. Still, the proportion of patients who respond to immunotherapy remains modest (~15% objective response rate across indications), as tumours have multiple means of immune evasion. The immune system is spatiotemporally controlled, so therapies that influence the immune system should be spatiotemporally controlled as well, in order to maximize the therapeutic index. Nanoparticles and biomaterials enable one to program the location, pharmacokinetics and co-delivery of immunomodulatory compounds, eliciting responses that cannot be achieved upon administration of such compounds in solution. The convergence of cancer immunotherapy, nanotechnology, bioengineering and drug delivery is opportune, as each of these fields has matured independently to the point that it can now be used to complement the others substantively and rationally, rather than modestly and empirically. As a result, unmet needs increasingly can be addressed with deductive intention. This Review explores how nanotechnology and related approaches are being applied to augmenting both endogenous leukocytes and adoptively transferred ones by informing specificity, influencing localization and improving function.
Although cancer immunotherapy can lead to durable outcomes, the percentage of patients who respond to this disruptive approach remains modest to date. Encouragingly, nanotechnology can enhance the ...efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics.
Nanotechnology can enhance the efficacy of small molecules and biologics for cancer immunotherapy.
Beyond mechanical markets Frydman, Roman; Frydman, Roman; Goldberg, Michael D
2011., 20110207, 2011, 2011-02-07, 20110101
eBook
In the wake of the global financial crisis that began in 2007, faith in the rationality of markets has lost ground to a new faith in their irrationality. The problem, Roman Frydman and Michael ...Goldberg argue, is that both the rational and behavioral theories of the market rest on the same fatal assumption--that markets act mechanically and economic change is fully predictable. In Beyond Mechanical Markets, Frydman and Goldberg show how the failure to abandon this assumption hinders our understanding of how markets work, why price swings help allocate capital to worthy companies, and what role government can and can't play.
Posing a major challenge to economic orthodoxy, Imperfect Knowledge Economics asserts that exact models of purposeful human behavior are beyond the reach of economic analysis. Roman Frydman and ...Michael Goldberg argue that the longstanding empirical failures of conventional economic models stem from their futile efforts to make exact predictions about the consequences of rational, self-interested behavior. Such predictions, based on mechanistic models of human behavior, disregard the importance of individual creativity and unforeseeable sociopolitical change. Scientific though these explanations may appear, they usually fail to predict how markets behave. And, the authors contend, recent behavioral models of the market are no less mechanistic than their conventional counterparts: they aim to generate exact predictions of "irrational" human behavior.
Frydman and Goldberg offer a long-overdue response to the shortcomings of conventional economic models. Drawing attention to the inherent limits of economists' knowledge, they introduce a new approach to economic analysis: Imperfect Knowledge Economics (IKE). IKE rejects exact quantitative predictions of individual decisions and market outcomes in favor of mathematical models that generate only qualitative predictions of economic change. Using the foreign exchange market as a testing ground for IKE, this book sheds new light on exchange-rate and risk-premium movements, which have confounded conventional models for decades.
Offering a fresh way to think about markets and representing a potential turning point in economics, Imperfect Knowledge Economics will be essential reading for economists, policymakers, and professional investors.
For many years there has been a debate about the role of the parietal lobe in the generation of behavior. Does it generate movement plans (intention) or choose objects in the environment for further ...processing? To answer this, we focus on the lateral intraparietal area (LIP), an area that has been shown to play independent roles in target selection for saccades and the generation of visual attention. Based on results from a variety of tasks, we propose that LIP acts as a priority map in which objects are represented by activity proportional to their behavioral priority. We present evidence to show that the priority map combines bottom-up inputs like a rapid visual response with an array of top-down signals like a saccade plan. The spatial location representing the peak of the map is used by the oculomotor system to target saccades and by the visual system to guide visual attention.
Cerebrovascular Disease in COVID-19 Goldberg, Michael F; Goldberg, Morton F; Cerejo, R ...
American journal of neuroradiology : AJNR,
07/2020, Letnik:
41, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Coronavirus disease 19 (COVID-19) is a pandemic originating in Wuhan, China, in December 2019. Early reports suggest that there are neurologic manifestations of COVID-19, including acute ...cerebrovascular disease. We report a case of COVID-19 with acute ischemic stroke. To our knowledge, this is the first reported case of COVID-19-related cerebral infarcts that includes brain imaging at multiple time points and CT angiography. There is a growing body of published evidence that complications of COVID-19 are not limited to the pulmonary system. Neuroradiologists should be aware of a wide range of neurologic manifestations, including cerebrovascular disease.
The role of the cerebellum in non-motor learning is poorly understood. Here, we investigated the activity of Purkinje cells (P-cells) in the mid-lateral cerebellum as the monkey learned to associate ...one arbitrary symbol with the movement of the left hand and another with the movement of the right hand. During learning, but not when the monkey had learned the association, the simple spike responses of P-cells reported the outcome of the animal’s most recent decision without concomitant changes in other sensorimotor parameters such as hand movement, licking, or eye movement. At the population level, P-cells collectively maintained a memory of the most recent decision throughout the entire trial. As the monkeys learned the association, the magnitude of this reward-related error signal approached zero. Our results provide a major departure from the current understanding of cerebellar processing and have critical implications for cerebellum’s role in cognitive control.
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•P-cells show a reinforcement error signal when monkeys learn a visuomotor association•The error signal is unrelated to movement kinematics and sensory events•The error signal is absent on wrong trials when monkeys perform a well-learned task•The magnitude of the reinforcement error signal decreases with learning
The cerebellum has been classically linked to correcting motor errors to optimize motor performance. Here, Sendhilnathan et al. show that mid-lateral cerebellar Purkinje cells carry error signals for reinforcement learning in their simple spikes, unrelated to movement kinematics or sensory events.
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the ...interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies.
The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) ...isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a selective growth advantage, is a promising target. Because many oncogenes impart a common alteration in cell metabolism, inhibition of the M2 isoform might be of broad applicability. We show that several small interfering (si) RNAs designed to target mismatches between the M2 and M1 isoforms confer specific knockdown of the former, resulting in decreased viability and increased apoptosis in multiple cancer cell lines but less so in normal fibroblasts or endothelial cells. In vivo delivery of siPKM2 additionally causes substantial tumor regression of established xenografts. Our results suggest that the inherent nucleotide-level specificity of siRNA can be harnessed to develop therapeutics that target isoform-specific exons in genes exhibiting differential splicing patterns in various cell types.
The neurology clinic needs monkey research Goldberg, Michael E.
Proceedings of the National Academy of Sciences - PNAS,
12/2019, Letnik:
116, Številka:
52
Journal Article
Recenzirano
Odprti dostop
This report discusses how a number of currently incurable diseases might be treated by advances developed as the result of current ongoing research on monkeys. The diseases discussed include ...Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, and stroke. Finally, the report discusses the devastating effect the animal rights movement and adverse publicity can have on basic neurobiological research on monkeys.
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