A novel view of ferritin in cancer.

Since its discovery more than 85 years ago, ferritin has principally been known as an iron storage protein. However, new roles, beyond iron storage, are being uncovered. Novel processes involving ferritin such as ferritinophagy and ferroptosis and as a cellular iron delivery protein not only expand our thinking on the range of contributions of this protein but present an opportunity to target these pathways in cancers. The key question we focus on within this review is whether ferritin modulation represents a useful approach for treating cancers. We discussed novel functions and processes of this protein in cancers. We are not limiting this review to cell intrinsic modulation of ferritin in cancers, but also focus on its utility in the trojan horse approach in cancer therapeutics. The novel functions of ferritin as discussed herein realize the multiple roles of ferritin in cell biology that can be probed for therapeutic opportunities and further research.

Implementation of medication reconciliation in outpatient cancer care.

BACKGROUND: Medication reconciliation (MedRec) is a process where providers work with patients to document and communicate comprehensive medication information by creating a complete medication list (best possible medication history (BPMH)) then reconciling it against what patient is actually taking to identify potential issues such as drug-drug interactions. We undertook an environmental scan of current MedRec practices in outpatient cancer care to inform a quality improvement project at our centre with the aim of 30% of patients having a BPMH or MedRec within 30 days of initiating treatment with systemic therapy. METHODS: We conducted semi-structured interviews with key stakeholders from 21 cancer centres across Canada, probing on current policies, and barriers and facilitators to MedRec. Guided by the findings of the scan, we then undertook a quality improvement project at our cancer centre, comprising six iterative improvement cycles. RESULTS: Most institutions interviewed had a process in place for collecting a BPMH (81%) and targeted patients initiating systemic therapy (59%); however, considerable practice variation was noted and completion of full MedRec was uncommon. Lack of resources, high patient volumes, lack of a common medical record spanning institutions and settings which limits access to medication records from external institutions and community pharmacies were identified as significant barriers. Despite navigating challenges related to the COVID-19 pandemic, we achieved 26.6% of eligible patients with a documented BPMH. However, uptake of full MedRec remained low whereby 4.7% of patients had a documented MedRec. CONCLUSIONS: Realising improvements to completion of MedRec in outpatient cancer care is possible but takes considerable time and iteration as the process is complex. Resource allocation and information sharing remain major barriers which need to be addressed in order to observe meaningful improvements in MedRec.

Effects of Antibody Response after Booster Vaccination on SARS-CoV-2 Breakthrough Infections and Disease Outcomes in Advanced Cancer Patients: A Prospective Analysis of the Vax-on-Third Study.

(1) Background: The clinical implications of COVID-19 outbreaks following SARS-CoV-2 vaccination in immunocompromised recipients are a worldwide concern. Cancer patients on active treatment remain at an increased risk of developing breakthrough infections because of waning immunity and the emergence of SARS-CoV-2 variants. There is a paucity of data on the effects of COVID-19 outbreaks on long-term survival outcomes in this population. (2) Methods: We enrolled 230 cancer patients who were on active treatment for advanced disease and had received booster dosing of an mRNA-BNT162b2 vaccine as part of the Vax-On-Third trial between September 2021 and October 2021. Four weeks after the third immunization, IgG antibodies against the spike receptor domain of SARS-CoV-2 were tested in all patients. We prospectively evaluated the incidence of breakthrough infections and disease outcomes. The coprimary endpoints were the effects of antibody titers on the development of breakthrough infections and the impact of COVID-19 outbreaks on cancer treatment failure. (3) Results: At a median follow-up of 16.3 months (95% CI 14.5-17.0), 85 (37%) patients developed SARS-CoV-2 infection. Hospitalization was required in 11 patients (12.9%) and only 2 (2.3%) deaths related to COVID-19 outbreaks were observed. Median antibody titers were significantly lower in breakthrough cases than in non-cases (291 BAU/mL (95% CI 210-505) vs. 2798 BAU/mL (95% CI 2323-3613), p < 0.001). A serological titer cut-off below 803 BAU/mL was predictive of breakthrough infection. In multivariate testing, antibody titers and cytotoxic chemotherapy were independently associated with an increased risk of outbreaks. Time-to-treatment failure after booster dosing was significantly shorter in patients who contracted SARS-CoV-2 infection (3.1 months (95% CI 2.3-3.6) vs. 16.2 months (95% CI 14.3-17.0), p < 0.001) and had an antibody level below the cut-off (3.6 months (95% CI 3.0-4.5) vs. 14.6 months (95% CI 11.9-16.3), p < 0.001). A multivariate Cox regression model confirmed that both covariates independently had a worsening effect on time-to-treatment failure. (4) Conclusions: These data support the role of vaccine boosters in preventing the incidence and severity of COVID-19 outbreaks. Enhanced humoral immunity after the third vaccination significantly correlates with protection against breakthrough infections. Strategies aimed at restraining SARS-CoV-2 transmission in advanced cancer patients undergoing active treatment should be prioritized to mitigate the impact on disease outcomes.

Comparison of immunogenicity for Sinovac-CoronaVac vaccine vs. natural infection during cancer treatment.

OBJECTIVE: Efficacy of the COVID-19 vaccines in cancer patients, especially during their active treatment, are lacking. Most of the studies in the literature compared the immunity in cancer patients with a cross-sectional cohort or retrospectively. Our study investigated Sinovac-CoronaVac COVID-19 vaccine immunogenicity and compared it with natural COVID-19 disease in cancer patients during their cancer therapy. PATIENTS AND METHODS: A total of 111 patients with cancer and who are on active treatment were included in the study. This is a single-center study and was designed prospectively. Two group of patients were included in the study, natural disease and vaccinated group. RESULTS: A total of 111 patients were included in the study, 34 of whom had natural COVID-19 disease. Antibody levels following the first dose vaccine were 0.4 (0-1.9) U/ml while after the second dose of vaccine were 2.6 (1.0-7.25) U/ml. Immunogenicity levels were 82.4% in the natural disease group and 75.8% in the vaccinated group after the second shot of the vaccine. Immunogenicity rate was significantly higher in non-chemotherapy (receiving immunotehrapy/targeted therapy or biologic agent) group compared to chemotherapy drug (92.9% vs. 63.3%, p=0.004). There was a difference between the antibody levels following the first and second vaccination [median (IQR): 0.3 (0-1.0) and 3.3 (2.0-6.7), p=0.001, respectively]. CONCLUSIONS: The present study revealed that the Sinovac-CoronaVac vaccine showed an acceptable immunogenicity following two shots in cancer patients who were receiving active systemic therapy. On the other hand, natural disease immunogenicity was higher than vaccinated group.

Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID.

Kinases can be grouped into 20 families which play a vital role as a regulator of neoplasia, metastasis, and cytokine suppression. Human genome sequencing has discovered more than 500 kinases. Mutations of the kinase itself or the pathway regulated by kinases leads to the progression of diseases such as Alzheimer's, viral infections, and cancers. Cancer chemotherapy has made significant leaps in recent years. The utilization of chemotherapeutic agents for treating cancers has become difficult due to their unpredictable nature and their toxicity toward the host cells. Therefore, targeted therapy as a therapeutic option against cancer-specific cells and toward the signaling pathways is a valuable avenue of research. SARS-CoV-2 is a member of the Betacoronavirus genus that is responsible for causing the COVID pandemic. Kinase family provides a valuable source of biological targets against cancers and for recent COVID infections. Kinases such as tyrosine kinases, Rho kinase, Bruton tyrosine kinase, ABL kinases, and NAK kinases play an important role in the modulation of signaling pathways involved in both cancers and viral infections such as COVID. These kinase inhibitors consist of multiple protein targets such as the viral replication machinery and specific molecules targeting signaling pathways for cancer. Thus, kinase inhibitors can be used for their anti-inflammatory, anti-fibrotic activity along with cytokine suppression in cases of COVID. The main goal of this review is to focus on the pharmacology of kinase inhibitors for cancer and COVID, as well as ideas for future development.

Synthetic and natural guanidine derivatives as antitumor and antimicrobial agents: A review.

Guanidines are fascinating small nitrogen-rich organic compounds, which have been frequently associated with a wide range of biological activities. This is mainly due to their interesting chemical features. For these reasons, for the past decades, researchers have been synthesizing and evaluating guanidine derivatives. In fact, there are currently on the market several guanidine-bearing drugs. Given the broad panoply of pharmacological activities displayed by guanidine compounds, in this review, we chose to focus on antitumor, antibacterial, antiviral, antifungal, and antiprotozoal activities presented by several natural and synthetic guanidine derivatives, which are undergoing preclinical and clinical studies from January 2010 to January 2023. Moreover, we also present guanidine-containing drugs currently in the market for the treatment of cancer and several infectious diseases. In the preclinical and clinical setting, most of the synthesized and natural guanidine derivatives are being evaluated as antitumor and antibacterial agents. Even though DNA is the most known target of this type of compounds, their cytotoxicity also involves several other different mechanisms, such as interference with bacterial cell membranes, reactive oxygen species (ROS) formation, mitochondrial-mediated apoptosis, mediated-Rac1 inhibition, among others. As for the compounds already used as pharmacological drugs, their main application is in the treatment of different types of cancer, such as breast, lung, prostate, and leukemia. Guanidine-containing drugs are also being used for the treatment of bacterial, antiprotozoal, antiviral infections and, recently, have been proposed for the treatment of COVID-19. To conclude, the guanidine group is a privileged scaffold in drug design. Its remarkable cytotoxic activities, especially in the field of oncology, still make it suitable for a deeper investigation to afford more efficient and target-specific drugs.

Safety of COVID-19 vaccines in subjects with solid tumor cancers receiving immune checkpoint inhibitors.

The incidence of severe immune-related adverse events (irAEs) in cancer subjects receiving immune checkpoint inhibitors (ICIs) following COVID-19 vaccination and the relationship between the incidence of severe irAE and the interval between COVID-19 vaccination and ICI dose have not been established. We performed a retrospective study evaluating the incidence of irAEs in solid tumor subjects receiving ICI therapy who received any COVID-19 vaccinations since FDA authorization. irAEs were defined as severe with one or more grade 3 or above events (CTCAE v5.0), multiple organ involvement, or requiring hospitalization for management. Two hundred and eighty-four subjects who received COVID vaccinations from December 2020 and February 2022 were included in this analysis [median age at vaccination 67 years (IQR 59.0-75.0); 67.3% male]. Twenty-nine subjects (10.2%) developed severe irAEs, of which 12 subjects (41.4%) received ICI monotherapy, 10 subjects (34.5%) received combination ICI therapy with nivolumab and ipilimumab, and 7 subjects (24.1%) received ICI plus VEGFR-TKI therapy. Hospitalization occurred in 62% of subjects with severe irAEs, with a median duration of 3 days (IQR: 3.0-7.5 days). Immunosuppressive therapy was required in 79.3%, with a median duration of 103 days (IQR: 42.0-179.0). ICI therapy was discontinued in 51.7% of subjects with severe irAE; dosing was held or interrupted in 34.5%. Among severe irAEs, the median interval between vaccination and ICI treatment closest to the occurrence of severe irAE was 15.5 days (IQR: 10.0-23.0). In solid tumor cancer subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.

The handling of biopharmaceuticals used in home-based therapy for cancer patients.

BACKGROUND: Due to their low bioavailability, biopharmaceuticals are typically administered via injection or infusion in a hospital setting. Home-based therapy could be a valuable alternative for cancer patients. However, when exposed to stressors, such as high or low temperatures, particles can form in the biopharmaceutical solution, compromising the safety and efficacy of the biopharmaceutical. AIM: This research investigated current practises with ready-to-administer biopharmaceuticals to determine if it is possible to offer cancer patients home-based therapy with monoclonal antibodies. METHODS: First, a questionnaire was conducted with the survey tool Survalyzer among Amsterdam UMC patients receiving immunoglobulins at home. Secondly, a web-based questionnaire (Survalyzer) was sent to pharmacists throughout Europe with a home-based therapy programme in place. RESULTS: The patient questionnaire (n = 52) showed that the biopharmaceutical is stored outside the recommended temperature range by 38% of the patients. Additionally, 17% of the patients do not recall getting any information on how to store their biopharmaceuticals, and 23% would like more information on the subject. Furthermore, the questionnaire amongst pharmacists (n = 21) showed that there is a lack of resources and logistical challenges when home-based therapy is applied to biopharmaceuticals used in cancer therapy. CONCLUSION: Home-based therapy with monoclonal antibodies for cancer patients is challenging to implement.

The Multifaceted Role of Glutathione S-Transferases in Health and Disease.

In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases.

Engineering Extracellular Vesicles as Delivery Systems in Therapeutic Applications.

Extracellular vesicles (EVs) are transport vesicles secreted by living cells and released into the extracellular environment. Recent studies have shown that EVs serve as "messengers" in intercellular and inter-organismal communication, in both normal and pathological processes. EVs, as natural nanocarriers, can deliver bioactivators in therapy with their endogenous transport properties. This review article describes the engineering EVs of sources, isolation method, cargo loading, boosting approach, and adjustable targeting of EVs. Furthermore, the review summarizes the recent progress made in EV-based delivery systems applications, including cancer, cardiovascular diseases, liver, kidney, nervous system diseases, and COVID-19 and emphasizes the obstacles and challenges of EV-based therapies and possible strategies.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Research progress on non-protein-targeted drugs for cancer therapy.

Non-protein target drugs, especially RNA-based gene therapies for treating hereditary diseases, have been recognized worldwide. As cancer is an insurmountable challenge, no miracle drug is currently available. With the advancements in the field of biopharmaceuticals, research on cancer therapy has gradually focused on non-protein target-targeted drugs, especially RNA therapeutics, including oligonucleotide drugs and mRNA vaccines. This review mainly summarizes the clinical research progress in RNA therapeutics and highlights that appropriate target selection and optimized delivery vehicles are key factors in increasing the effectiveness of cancer treatment in vivo.

Impact of BSG/CD147 gene expression on diagnostic, prognostic and therapeutic strategies towards malignant cancers and possible susceptibility to SARS-CoV-2.

BACKGROUND: BSG (CD147) is a member of the immunoglobulin superfamily that shows roles for potential prognostics and therapeutics for metastatic cancers and SARS-CoV-2 invasion for COVID-19. The susceptibility of malignant cancers to SARS-CoV-2 as well as the correlations between disease outcome and BSG expression in tumor tissues have not been studied in depth. METHODS: In this study, we explored the BSG expression profile, survival correlation, DNA methylation, mutation, diagnostics, prognostics, and tumor-infiltrating lymphocytes (TILs) from different types of cancer tissues with corresponding healthy tissues. In vitro studies for cordycepin (CD), N6-(2-hydroxyethyl) adenosine (HEA), N6, N6-dimethyladenosine (m62A) and 5'-uridylic acid (UMP) on BSG expression were also conducted. RESULTS: We revealed that BSG is conserved among different species, and significantly upregulated in seven tumor types, including ACC, ESCA, KICH, LIHC, PAAD, SKCM and THYM, compared with matched normal tissues, highlighting the susceptibility of these cancer patients to SARS-CoV-2 invasion, COVID-19 severity and progression of malignant cancers. High expression in BSG was significantly correlated with a short OS in LGG, LIHC and OV patients, but a long OS in KIRP patients. Methylation statuses in the BSG promoter were significantly higher in BRCA, HNSC, KIRC, KIRP, LUSC, PAAD, and PRAD tumor tissues, but lower in READ. Four CpGs in the BSG genome were identified as potential DNA methylation biomarkers which could be used to predict malignant cancers from normal individuals. Furthermore, a total of 65 mutation types were found, in which SARC showed the highest mutation frequency (7.84%) and THYM the lowest (0.2%). Surprisingly, both for disease-free and progression-free survival in pan-cancers were significantly reduced after BSG mutations. Additionally, a correlation between BSG expression and immune lymphocytes of CD56bright natural killer cell, CD56dim natural killer cell and monocytes, MHC molecules of HLA-A, HLA-B, HLA-C and TAPBP, immunoinhibitor of PVR, PVRL2, and immunostimulators of TNFRSF14, TNFRSF18, TNFRSF25, and TNFSF9, was revealed in most cancer types. Moreover, BSG expression was downregulated by CD, HEA, m62A or UMP in cancer cell lines, suggesting therapeutic potentials for interfering entry of SARS-CoV-2. CONCLUSIONS: Altogether, our study highlights the values of targeting BSG for diagnostic, prognostic and therapeutic strategies to fight malignant cancers and COVID-19. Small molecules CD, HEA, m62A and UMP imply therapeutic potentials in interfering with entry of SARS-CoV-2 and progression of malignant cancers.

A "trained immunity" inducer-adjuvanted nanovaccine reverses the growth of established tumors in mice.

Innate immune cells are critical in antitumor immune surveillance and the development of antitumor adaptive cellular immunity. Trained innate immune cells demonstrate immune memory-like characteristics, producing more vigorous immune responses to secondary homologous or heterologous stimuli. This study aimed to investigate whether inducing trained immunity is beneficial when using a tumor vaccine to promote antitumor adaptive immune responses. A biphasic delivery system was developed with the trained immunity inducer Muramyl Dipeptide (MDP) and specific tumor antigen human papillomavirus (HPV) E7 peptide encapsulated by poly(lactide-co-glycolide)-acid(PLGA) nanoparticles (NPs), and the NPs along with another trained immunity agonist, ß-glucan, were further embedded in a sodium alginate hydrogel. The nanovaccine formulation demonstrated a depot effect for E7 at the injection site and targeted delivery to the lymph nodes and dendritic cells (DCs). The antigen uptake and maturation of DCs were significantly promoted. A trained immunity phenotype, characterized by increased production of IL-1ß, IL-6, and TNF-α, was induced in vitro and in vivo in response to secondary homologous or heterologous stimulation. Furthermore, prior innate immune training enhanced the antigen-specific INF-γ-expressing immune cell response elicited by subsequent stimulation with the nanovaccine. Immunization with the nanovaccine completely inhibited the growth of TC-1 tumors and even abolished established tumors in mice. Mechanistically, the inclusion of ß-glucan and MDP significantly enhanced the responses of tumor-specific effector adaptive immune cells. The results strongly suggest that the controlled release and targeted delivery of an antigen and trained immunity inducers with an NP/hydrogel biphasic system can elicit robust adaptive immunity, which provides a promising tumor vaccination strategy.

Beyond "Psychotropic": Repurposing Psychiatric Drugs for COVID-19, Alzheimer's Disease, and Cancer.

Importance: "Psychotropic" drugs have widespread reach and impact throughout the brain and body. Thus, many of these drugs could be repurposed for non-psychiatric indications of high public health impact.Observations: The selective serotonin reuptake inhibitor (SSRI) fluvoxamine was shown efficacious as a COVID-19 treatment based on randomized controlled trials (RCTs), and a benefit of other antidepressants has been posited based on observational and preclinical studies. In this review, we illuminate features of SSRIs and other psychiatric drugs that make them candidates to repurpose for non-psychiatric indications. We summarize research that led to fluvoxamine's use in COVID-19 and provide guidance on how to use it safely. We summarize studies suggestive of benefit of other antidepressants versus COVID-19 and long COVID. We also describe putative mechanisms of psychiatric drugs in treating long COVID, Alzheimer's disease, cancer, and other conditions.Conclusion and Relevance: There is a potentially great clinical and public health impact of psychotropic drug repurposing. Challenges exist to such repurposing efforts, but solutions exist for researchers, regulators, and funders that overcome these challenges.