The medial prefrontal cortex during flexible decisions: Evidence for its role in distinct working memory processes.

During decisions that involve working memory, task-related information must be encoded, maintained across delays, and retrieved. Few studies have attempted to causally disambiguate how different brain structures contribute to each of these components of working memory. In the present study, we used transient optogenetic disruptions of rat medial prefrontal cortex (mPFC) during a serial spatial reversal learning (SSRL) task to test its role in these specific working memory processes. By analyzing numerous performance metrics, we found: (1) mPFC disruption impaired performance during only the choice epoch of initial discrimination learning of the SSRL task; (2) mPFC disruption impaired performance in dissociable ways across all task epochs (delay, choice, return) during flexible decision-making; (3) mPFC disruption resulted in a reduction of the typical vicarious-trial-and-error rate modulation that was related to changes in task demands. Taken together, these findings suggest that the mPFC plays an outsized role in working memory retrieval, becomes involved in encoding and maintenance when recent memories conflict with task demands, and enables animals to flexibly utilize working memory to update behavior as environments change.

Type of anesthesia for cancer resection surgery: No differential impact on cancer recurrence in mouse models of breast cancer.

BACKGROUND: Surgery is essential for curative treatment of solid tumors. Evidence from recent retrospective clinical analyses suggests that use of propofol-based total intravenous anesthesia during cancer resection surgery is associated with improved overall survival compared to inhaled volatile anesthesia. Evaluating these findings in prospective clinical studies is required to inform definitive clinical guidelines but will take many years and requires biomarkers to monitor treatment effect. Therefore, we examined the effect of different anesthetic agents on cancer recurrence in mouse models of breast cancer with the overarching goal of evaluating plausible mechanisms that could be used as biomarkers of treatment response. METHODS: To test the hypothesis that volatile anesthesia accelerates breast cancer recurrence after surgical resection of the primary tumor, we used three mouse models of breast cancer. We compared volatile sevoflurane anesthesia with intravenous propofol anesthesia and used serial non-invasive bioluminescent imaging to track primary tumor recurrence and metastatic recurrence. To determine short-term perioperative effects, we evaluated the effect of anesthesia on vascular integrity and immune cell changes after surgery in animal models. RESULTS: Survival analyses found that the kinetics of cancer recurrence and impact on survival were similar regardless of the anesthetic agent used during cancer surgery. Vascular permeability, immune cell infiltration and cytokine profiles showed no statistical difference after resection with inhaled sevoflurane or intravenous propofol anesthesia. CONCLUSIONS: These preclinical studies found no evidence that choice of anesthetic agent used during cancer resection surgery affected either short-term perioperative events or long-term cancer outcomes in mouse models of breast cancer. These findings raise the possibility that mouse models do not recapitulate perioperative events in cancer patients. Nonetheless, the findings suggest that future evaluation of effects of anesthesia on cancer outcomes should focus on cancer types other than breast cancer.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

RMG Database for Chemical Property Prediction.

The Reaction Mechanism Generator (RMG) database for chemical property prediction is presented. The RMG database consists of curated datasets and estimators for accurately predicting the parameters necessary for constructing a wide variety of chemical kinetic mechanisms. These datasets and estimators are mostly published and enable prediction of thermodynamics, kinetics, solvation effects, and transport properties. For thermochemistry prediction, the RMG database contains 45 libraries of thermochemical parameters with a combination of 4564 entries and a group additivity scheme with 9 types of corrections including radical, polycyclic, and surface absorption corrections with 1580 total curated groups and parameters for a graph convolutional neural network trained using transfer learning from a set of >130 000 DFT calculations to 10 000 high-quality values. Correction schemes for solvent-solute effects, important for thermochemistry in the liquid phase, are available. They include tabulated values for 195 pure solvents and 152 common solutes and a group additivity scheme for predicting the properties of arbitrary solutes. For kinetics estimation, the database contains 92 libraries of kinetic parameters containing a combined 21 000 reactions and contains rate rule schemes for 87 reaction classes trained on 8655 curated training reactions. Additional libraries and estimators are available for transport properties. All of this information is easily accessible through the graphical user interface at https://rmg.mit.edu. Bulk or on-the-fly use can be facilitated by interfacing directly with the RMG Python package which can be installed from Anaconda. The RMG database provides kineticists with easy access to estimates of the many parameters they need to model and analyze kinetic systems. This helps to speed up and facilitate kinetic analysis by enabling easy hypothesis testing on pathways, by providing parameters for model construction, and by providing checks on kinetic parameters from other sources.

An In Vivo Mouse Model of Total Intravenous Anesthesia during Cancer Resection Surgery.

Anesthesia is a routine component of cancer care that is used for diagnostic and therapeutic procedures. The anesthetic technique has recently been implicated in impacting long-term cancer outcomes, possibly through modulation of adrenergic-inflammatory responses that impact cancer cell behavior and immune cell function. Emerging evidence suggests that propofol-based total intravenous anesthesia (TIVA) may be beneficial for long-term cancer outcomes when compared to inhaled volatile anesthesia. However, the available clinical findings are inconsistent. Preclinical studies that identify the underlying mechanisms involved are critically needed to guide the design of clinical studies that will expedite insight. Most preclinical models of anesthesia have been extrapolated from the use of anesthesia in in vivo research and are not optimally designed to study the impact of anesthesia itself as the primary endpoint. This paper describes a method for delivering propofol-TIVA anesthesia in a mouse model of breast cancer resection that replicates key aspects of clinical delivery in cancer patients. The model can be used to study mechanisms of action of anesthesia on cancer outcomes in diverse cancer types and can be extrapolated to other non-cancer areas of preclinical anesthesia research.

Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses.

The sympathetic nervous system (SNS) controls various physiological functions via the neurotransmitter noradrenaline. Activation of the SNS in response to psychological or physical stress is frequently associated with weakened immunity. Here, we investigated how adrenoceptor signaling influences leukocyte behavior. Intravital two-photon imaging after injection of noradrenaline revealed transient inhibition of CD8+ and CD4+ T cell locomotion in tissues. Expression of ß-adrenergic receptor in hematopoietic cells was not required for NA-mediated inhibition of motility. Rather, chemogenetic activation of the SNS or treatment with adrenergic receptor agonists induced vasoconstriction and decreased local blood flow, resulting in abrupt hypoxia that triggered rapid calcium signaling in leukocytes and halted cell motility. Oxygen supplementation reversed these effects. Treatment with adrenergic receptor agonists impaired T cell responses induced in response to viral and parasitic infections, as well as anti-tumor responses. Thus, stimulation of the SNS impairs leukocyte mobility, providing a mechanistic understanding of the link between adrenergic receptors and compromised immunity.

Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients.

PURPOSE: The sympathetic nervous system drives breast cancer progression through ß-adrenergic receptor signalling. This discovery has led to the consideration of cardiac ß-blocker drugs as novel strategies for anticancer therapies. Carvedilol is a ß-blocker used in the management of cardiovascular disorders, anxiety, migraine and chemotherapy-induced cardiotoxicity. However, little is known about how carvedilol affects cancer-related outcomes. METHODS: To address this, we investigated the effects of carvedilol on breast cancer cell lines, in mouse models of breast cancer and in a large cohort of patients with breast cancer (n = 4014). RESULTS: Treatment with carvedilol blocked the effects of sympathetic nervous system activation, reducing primary tumour growth and metastasis in a mouse model of breast cancer and preventing invasion by breast cancer cell lines. A retrospective analysis found that women using carvedilol at breast cancer diagnosis (n = 136) had reduced breast cancer-specific mortality compared with women who did not (n = 3878) (5-year cumulative incidence of breast cancer deaths: 3.1% versus 5.7%; p = 0.024 and 0.076 from univariate and multivariable analyses, respectively) after a median follow-up of 5.5 years. CONCLUSIONS: These findings provide a rationale to further explore the use of the ß-blocker carvedilol as a novel strategy to slow cancer progression.