Virus-Induced Epilepsy vs. Epilepsy Patients Acquiring Viral Infection: Unravelling the Complex Relationship for Precision Treatment.

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.

Dual Drug Repurposing: The Example of Saracatinib.

Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.

Repurposing of the Drug Tezosentan for Cancer Therapy.

Tezosentan is a vasodilator drug that was originally developed to treat pulmonary arterial hypertension. It acts by inhibiting endothelin (ET) receptors, which are overexpressed in many types of cancer cells. Endothelin-1 (ET1) is a substance produced by the body that causes blood vessels to narrow. Tezosentan has affinity for both ETA and ETB receptors. By blocking the effects of ET1, tezosentan can help to dilate blood vessels, improve the blood flow, and reduce the workload on the heart. Tezosentan has been found to have anticancer properties due to its ability to target the ET receptors, which are involved in promoting cellular processes such as proliferation, survival, neovascularization, immune cell response, and drug resistance. This review intends to demonstrate the potential of this drug in the field of oncology. Drug repurposing can be an excellent way to improve the known profiles of first-line drugs and to solve several resistance problems of these same antineoplastic drugs.

The Involvement of Hypoxia in the Response of Neuroblastoma Cells to the Exposure of Atorvastatin.

Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment. Atorvastatin is a type of statin with several potentialities as an anti-cancer agent, supported by several studies. Our study aimed to explore the effect of this drug in SH-SY5Y human neuroblastoma cells. Additionally, we also aimed to understand how this drug acts under hypoxia and the inhibition of hypoxia-inducible factor-1 (HIF-1). For that purpose, we assessed cellular viability/morphology after exposure to different concentrations of atorvastatin, with or without chemically induced hypoxia with chloride cobalt (CoCl2) and with or without echinomycin (HIF-1α inhibitor). Our results supported the cytotoxic effects of atorvastatin. Additionally, we also revealed that besides these effects, under hypoxia, this drug induced proliferation of the neuroblastoma cells, supporting the importance of different stimuli and environment on the effect of drugs on cancer cells.

Evolution of Antiretroviral Drug Rilpivirine and Approach to Oncology.

Rilpivirine is an antiretroviral drug used to treat AIDS worldwide. The drug is a non-nucleoside reverse transcriptase inhibitor that halts the cDNA elongation process and, thus, the capacity of the HIV-1 virus to replicate. With the new wave of drug repurposing in recent years, rilpivirine has been studied in this regard. This drug is useful in Zika virus treatment, with in vivo results indicating regression in neuronal effects often associated with this infection. Several cancer types have also been researched, from breast to leukemia and pancreatic cancer, and rilpivirine has proved to have inhibitory effects in various cell lines with low concentrations, causing cellular death, apoptosis, and cell cycle arrest. The pathways are not yet established, but some works have hypothesized and demonstrated that rilpivirine causes inhibition of Aurora A kinase and has effects on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and the vascular endothelial growth factors-receptors (VEGFs-VEGFRs) pathway, which are known to be altered in cancer and tumors and can be targeted for cancer treatment. Further testing and clinical trials are needed, but this review demonstrates the potential of rilpivirine's repurposing for cancer treatment.

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer.

Worldwide, prostate cancer (PC) is the second most frequent cancer among men and the fifth leading cause of death; moreover, standard treatments for PC have several issues, such as side effects and mechanisms of resistance. Thus, it is urgent to find drugs that can fill these gaps, and instead of developing new molecules requiring high financial and time investments, it would be useful to select non-cancer approved drugs that have mechanisms of action that could help in PC treatment, a process known as repurposing drugs. In this review article, drugs that have potential pharmacological efficacy are compiled to be repurposed for PC treatment. Thus, these drugs will be presented in the form of pharmacotherapeutic groups, such as antidyslipidemic drugs, antidiabetic drugs, antiparasitic drugs, antiarrhythmic drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, antidepressant drugs, antihypertensive drugs, antifungal drugs, immunosuppressant drugs, antipsychotic drugs, antiepileptic and anticonvulsant drugs, bisphosphonates and drugs for alcoholism, among others, and we will discuss their mechanisms of action in PC treatment.

How Can the Microbiome Induce Carcinogenesis and Modulate Drug Resistance in Cancer Therapy?

Over the years, cancer has been affecting the lives of many people globally and it has become one of the most studied diseases. Despite the efforts to understand the cell mechanisms behind this complex disease, not every patient seems to respond to targeted therapies or immunotherapies. Drug resistance in cancer is one of the limiting factors contributing to unsuccessful therapies; therefore, understanding how cancer cells acquire this resistance is essential to help cure individuals affected by cancer. Recently, the altered microbiome was observed to be an important hallmark of cancer and therefore it represents a promising topic of cancer research. Our review aims to provide a global perspective of some cancer hallmarks, for instance how genetic and epigenetic modifications may be caused by an altered human microbiome. We also provide information on how an altered human microbiome can lead to cancer development as well as how the microbiome can influence drug resistance and ultimately targeted therapies. This may be useful to develop alternatives for cancer treatment, i.e., future personalized medicine that can help in cases where traditional cancer treatment is unsuccessful.

Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions.

This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This paper sheds light on the latest research advancements and potential treatment strategies by examining the historical context of HERVs and their involvement in critical biological processes such as embryonic development, immune response, and disease progression. This review covers computational modeling for drug-target binding assessment, systems biology modeling for simulating HERV-K viral cargo dynamics, and using antiviral drugs to combat HERV-induced diseases. The findings presented in this review contribute to our understanding of HERV-mediated disease mechanisms and provide insights into future therapeutic approaches. They emphasize why HERV-K holds significant promise as a biomarker and a target.

Understanding Lamotrigine's Role in the CNS and Possible Future Evolution.

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.

The Effect of the Stress Induced by Hydrogen Peroxide and Corticosterone on Tryptophan Metabolism, Using Human Neuroblastoma Cell Line (SH-SY5Y).

L-tryptophan (L-Trp) is an important amino acid in several physiological mechanisms, being metabolized into two important pathways: the kynurenine and the serotonin (5-HT) pathways. It is important in processes such as mood and stress response, the 5-HT pathway begins with the conversion of L-Trp to 5-hydroxytryptophan (5-HTP), that is metabolized into 5-HT, converted to melatonin or to 5-hydroxyindoleacetic acid (5-HIAA). Disturbances in this pathway are reported to be connected with oxidative stress and glucocorticoid-induced stress, are important to explore. Thus, our study aimed to understand the role of hydrogen peroxide (H2O2) and corticosterone (CORT)-induced stress on the serotonergic pathway of L-Trp metabolism, and on SH-SY5Y cells, focusing on the study of L-Trp, 5-HTP, 5-HT, and 5-HIAA in combination with H2O2 or CORT. We evaluated the effect of these combinations on cellular viability, morphology, and on the extracellular levels of the metabolites. The data obtained highlighted the different ways that stress induction led to different extracellular medium concentration of the studied metabolites. These distinct chemical transformations did not lead to differences in cell morphology/viability. Additionally, serotonin may be the most sensitive metabolite to the exposure to the different stress inducers, being more promissory to study conditions associated with cellular stress.

Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis.

Cancer is regard as one of the key factors of mortality and morbidity in the world. Treatment is mainly based on chemotherapeutic drugs that, when used in targeted therapies, have serious side effects. 5-fluorouracil (5-FU) is a drug commonly used against colorectal cancer (CRC), despite its side effects. Combination of this compound with natural products is a promising source in cancer treatment research. In recent years, propolis has become the subject of intense pharmacological and chemical studies linked to its diverse biological properties. With a complex composition rich in phenolic compounds, propolis is described as showing positive or synergistic interactions with several chemotherapeutic drugs. The present work evaluated the in vitro cytotoxic activity of the most representative propolis types, such as green, red and brown propolis, in combination with chemotherapeutic or CNS drugs on HT-29 colon cancer cell lines. The phenolic composition of the propolis samples was evaluated by LC-DAD-ESI/MSn analysis. According to the type of propolis, the composition varied; green propolis was rich in terpenic phenolic acids and red propolis in polyprenylated benzophenones and isoflavonoids, while brown propolis was composed mainly of flavonoids and phenylpropanoids. Generally, for all propolis types, the results demonstrated that combing propolis with 5-FU and fluphenazine successfully enhances the in vitro cytotoxic activity. For green propolis, the combination demonstrated an enhancement of the in vitro cytotoxic effect compared to green propolis alone, at all concentrations, while for brown propolis, the combination in the concentration of 100 µg/mL gave a lower number of viable cells, even when compared with 5-FU or fluphenazine alone. The same was observed for the red propolis combination, but with a higher reduction in cell viability. The combination index, calculated based on the Chou-Talalay method, suggested that the combination of 5-FU and propolis extracts had a synergic growth inhibitory effect in HT-29 cells, while with fluphenazine, only green and red propolis, at a concentration of 100 µg/mL, presented synergism.

Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells.

Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01-100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.

Drug Metabolism for the Identification of Clinical Biomarkers in Breast Cancer.

Breast cancer is classified into four major molecular subtypes, and is considered a heterogenous disease. The risk profiles and treatment of breast cancer differ according to these subtypes. Early detection dramatically improves the prospects of successful treatment, resulting in a reduction in overall mortality rates. However, almost 30% of women primarily diagnosed with the early-stage disease will eventually develop metastasis or resistance to chemotherapies. Immunotherapies are among the most promising cancer treatment options; however, long-term clinical benefit has only been observed in a small subset of responding patients. The current strategies for diagnosis and treatment rely heavily on histopathological examination and molecular diagnosis, disregarding the tumor microenvironment and microbiome involving cancer cells. In this review, we aim to praise the use of pharmacogenomics and pharmacomicrobiomics as a strategy to identify potential biomarkers for guiding and monitoring therapy in real-time. The finding of these biomarkers can be performed by studying the metabolism of drugs, more specifically, immunometabolism, and its relationship with the microbiome, without neglecting the information provided by genetics. A larger understanding of cancer biology has the potential to improve patient care, enable clinical decisions, and deliver personalized medicine.

Salbutamol in the Management of Asthma: A Review.

Asthma is a common inflammatory disease of the lungs. The prevalence of asthma is increasing worldwide, and the tendency indicates that the number of asthma sufferers will soar in the coming years for several reasons, in particular, the lifestyles we have adopted that expose us to risk factors. Salbutamol is the first selective short-acting ß2-agonist (SABA) used as an alternative reliever in the treatment of asthma. Its therapeutic effect is based on its potent smooth muscle relaxant properties, which allow the inhibition of bronchial smooth muscle contraction and subsequent bronchodilation. Salbutamol can be administered orally, intravenously (IV), intramuscularly (IM), subcutaneously, or by inhalation. For this reason, the pharmacokinetic (PK) parameters-absorption, distribution, metabolism, and elimination-are highly diverse and, consequently, the efficacy and adverse effects also differ between each formulation. Here, we review the pharmacological profile of different salbutamol formulations, focusing on their efficacy and adverse effects for its original application, asthma.

Repurposing Alone and in Combination of the Antiviral Saquinavir with 5-Fluorouracil in Prostate and Lung Cancer Cells.

Prostate and lung cancers are among the most common cancer types, and they still need more therapeutics. For this purpose, saquinavir (SAQ) was tested alone and in combination with 5-fluorouracil (5-FU). PC-3 and A549 cells were exposed to increasing concentrations of both drugs alone or in combination, with simultaneous or sequential administration. Cell viability was obtained using the MTT assay and synergism values using CompuSyn software. Results showed that SAQ was the more cytotoxic of both drugs in PC-3 cells, while 5-FU was the most cytotoxic in A549 cells. When these drugs were used in combination, the more synergistic combination in PC-3 cells was the IC50 of SAQ with various concentrations of 5-FU, particularly when 5-FU was only applied 24 h later. Meanwhile for A549 the most promising combination was 5-FU with delayed SAQ, but with a weaker effect than all combinations demonstrated in PC-3 cells. These results demonstrate that SAQ could be used as a new repurposed drug for the treatment of prostate cancer and this treatment potential could be even greater if SAQ is combined with the anticancer drug 5-FU, while for lung cancer it is not as efficient and, therefore, not of as much interest.

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways.

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.

Drug Repurposing in Cancer Therapy: Influence of Patient's Genetic Background in Breast Cancer Treatment.

Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients' characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients' genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.

The Antineoplastic Effect of Carboplatin Is Potentiated by Combination with Pitavastatin or Metformin in a Chemoresistant High-Grade Serous Carcinoma Cell Line.

The combination of Carboplatin with Paclitaxel is the mainstay treatment for high-grade serous carcinoma; however, many patients with advanced disease undergo relapse due to chemoresistance. Drug repurposing coupled with a combination of two or more compounds with independent mechanisms of action has the potential to increase the success rate of the antineoplastic treatment. The purpose of this study was to explore whether the combination of Carboplatin with repurposed drugs led to a therapeutic benefit. Hence, we assessed the cytotoxic effects of Carboplatin alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumoral models, i.e., Carboplatin (OVCAR8) and Carboplatin-Paclitaxel (OVCAR8 PTX R P) chemoresistant cell lines and in a non-tumoral (HOSE6.3) cell line. Cellular viability was measured using the Presto Blue assay, and the synergistic interactions were evaluated using the Chou-Talalay, Bliss Independence and Highest Single Agent reference models. Combining Carboplatin with Pitavastatin or Metformin displayed the highest cytotoxic effect and the strongest synergism among all combinations for OVCAR8 PTX R P cells, resulting in a chemotherapeutic effect superior to Carboplatin as a single agent. Concerning HOSE6.3 cells, combining Carboplatin with almost all the repurposed drugs demonstrated a safe pharmacological profile. Overall, we propose that Pitavastatin or Metformin could act synergistically in combination with Carboplatin for the management of high-grade serous carcinoma patients with a Carboplatin plus Paclitaxel resistance profile.

Cell Model of Depression: Reduction of Cell Stress with Mirtazapine.

Depression is a very prevalent and complex disease. This condition is associated with a high rate of relapse, making its treatment a challenge. Thus, an intensive investigation of this disease and its treatment is necessary. In this work, through cell viability assays (MTT and neutral red assays) and alkaline comet assays, we aimed to test the induction of stress in human SH-SY5Y cells through the application of hydrocortisone and hydrogen peroxide and to test the reversal or attenuation of this stress through the application of mirtazapine to the cells. Our results demonstrated that hydrogen peroxide, and not hydrocortisone, can induce cellular stress, as evidenced by DNA damage and a global cellular viability reduction, which were alleviated by the antidepressant mirtazapine. The establishment of a cellular model of depression through stress induction is important to study new possibilities of treatment of this disease using cell cultures.

A Second Life for MAP, a Model Amphipathic Peptide.

Cell-penetrating peptides (CPP) have been shown to be efficient in the transport of cargoes into the cells, namely siRNA and DNA, proteins and peptides, and in some cases, small therapeutics. These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an α-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.