Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4.

The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2'-methylenebis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl)ethane, and 2,2'-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and 'DNA-templated DNA replication' which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.

The Effect of Plastic-Related Compounds on Transcriptome-Wide Gene Expression on CYP2C19-Overexpressing HepG2 Cells.

In recent years, plastic and especially microplastic in the oceans have caused huge problems to marine flora and fauna. Recently, such particles have also been detected in blood, breast milk, and placenta, underlining their ability to enter the human body, presumably via the food chain and other yet-unknown mechanisms. In addition, plastic contains plasticizers, antioxidants, or lubricants, whose impact on human health is also under investigation. At the cellular level, the most important enzymes involved in the metabolism of xenobiotic compounds are the cytochrome P450 monooxygenases (CYPs). Despite their extensive characterization in the maintenance of cellular balance, their interactions with plastic and related products are unexplored. In this study, the possible interactions between several plastic-related compounds and one of the most important cytochromes, CYP2C19, were analyzed. By applying virtual compound screening and molecular docking to more than 1000 commercially available plastic-related compounds, we identified candidates that are likely to interact with this protein. A growth inhibition assay confirmed their cytotoxic activity on a CYP2C19-transfected hepatic cell line. Subsequently, we studied the effect of the selected compounds on the transcriptome-wide gene expression level by conducting RNA sequencing. Three candidate molecules were identified, i.e., 2,2'-methylene bis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl) ethane, and 2,2'-methylene bis(6-cyclohexyl-4-methylphenol)), which bound with a high affinity to CYP2C19 in silico. They exerted a profound cytotoxicity in vitro and interacted with several metabolic pathways, of which the 'cholesterol biosynthesis process' was the most affected. In addition, other affected pathways involved mitosis, DNA replication, and inflammation, suggesting an increase in hepatotoxicity. These results indicate that plastic-related compounds could damage the liver by affecting several molecular pathways.

Treatment and secondary prophylaxis of venous thromboembolism in cancer patients.

Cancer-associated thrombosis (CAT) adversely affects the quality of life and survival of people with cancer. A holistic approach is optimal for the treatment and secondary prophylaxis of venous thromboembolism (VTE) including shared decision-making around anticoagulation, considering individual risk factors for VTE recurrence, morbidities from VTE, and resources available in cancer centres around the world. Taking a global perspective on availability and cost, this paper guides the reader through the wider aspects of treatment and secondary thromboprophylaxis which, in turn, influence the recent international guidelines.

Inpatient primary prophylaxis of cancer-associated thromboembolism (CAT).

PURPOSE: Cancer-associated thrombosis (CAT) increases morbidity and mortality in oncology patients. The risk of CAT is increased with hospitalization for acute medical illness. The goal of this review will be to examine the available evidence for (1) risk assessment and (2) primary thromboprophylaxis, (3) international published guideline recommendations, and (4) future directions to manage oncology patients admitted for an acute medical illness. METHODS: A review was performed for each subject to gather information on the available evidence and recommendations available for oncology patients hospitalized for an acute medical illness. RESULTS: Risk assessments for thrombosis are primarily developed and validated in the general population. There is not a risk assessment that has specifically been developed and validated in oncology patients hospitalized for an acute medical illness. Most evidence for thromboprophylaxis of oncology patients is from sub-group analysis of larger randomized-controlled trials in the general population. Evidence is conflicting and suggests an individualized approach evaluating the risk-benefit of thromboprophylaxis. The strength of recommendations of international guidelines is limited because of the available evidence. Guidelines usually recommend utilizing and/or offering thromboprophylaxis to oncology patients hospitalized for an acute medical illness barring contraindications. Future evidence needs to improve risk assessments and knowledge of the appropriate agent, dose, and duration of thromboprophylaxis if indicated. CONCLUSION: Evidence for risk assessments and primary prophylaxis for oncology patients hospitalized for acute medical illness appears limited, with many research opportunities available to improve understanding on management of this patient population.

Risk factors associated with venous thromboembolism in breast cancer: a narrative review.

PURPOSE: To date, there is no universally acceptable risk assessment tool in clinical practice that accurately estimates the risk of venous thromboembolism (VTE) in patients with breast cancer, despite the large number of published studies. Thus, the aim of this narrative review was to summarize the most relevant risk factors for VTE in these patients. METHODS: We searched Ovid Embase and Ovid MEDLINE, from inception to March 26, 2021, to identify all articles that focused on breast cancer and multiple thromboembolic diseases. We also searched the references section of relevant articles to identify studies. We did not include case reports or case series with small sample size, N < 20. RESULTS: VTE in patients with breast cancer was strongly associated with patient-, tumor-, and non-tumor-related risk factors, such as age, disease stage, central catheter placement, and chemotherapy and tamoxifen use, especially within 2 years of breast cancer diagnosis. CDK inhibitors are emerging factors that may also increase the risk of VTE. CONCLUSIONS: The risk of VTE in patients with breast cancer depends on various patient-, tumor-, and non-tumor-related risk factors. Identifying these risk factors during breast cancer diagnosis and treatment is essential in developing a practical dynamic predictive tool that can help individualize strategies to prevent VTE.

Identification of Cuproptosis-Associated Prognostic Gene Expression Signatures from 20 Tumor Types.

We investigated the mRNA expression of 124 cuproptosis-associated genes in 7489 biopsies from 20 different tumor types of The Cancer Genome Atlas (TCGA). The KM plotter algorithm has been used to calculate Kaplan-Meier statistics and false discovery rate (FDR) corrections. Interaction networks have been generated using Ingenuity Pathway Analysis (IPA). High mRNA expression of 63 out of 124 genes significantly correlated with shorter survival times of cancer patients across all 20 tumor types. IPA analyses revealed that their gene products were interconnected in canonical pathways (e.g., cancer, cell death, cell cycle, cell signaling). Four tumor entities showed a higher accumulation of genes than the other cancer types, i.e., renal clear cell carcinoma (n = 21), renal papillary carcinoma (n = 13), kidney hepatocellular carcinoma (n = 13), and lung adenocarcinoma (n = 9). These gene clusters may serve as prognostic signatures for patient survival. These signatures were also of prognostic value for tumors with high mutational rates and neoantigen loads. Cuproptosis is of prognostic significance for the survival of cancer patients. The identification of specific gene signatures deserves further exploration for their clinical utility in routine diagnostics.

Anti-Inflammatory and Cancer-Preventive Potential of Chamomile (Matricaria chamomilla L.): A Comprehensive In Silico and In Vitro Study.

BACKGROUND AND AIM: Chamomile tea, renowned for its exquisite taste, has been appreciated for centuries not only for its flavor but also for its myriad health benefits. In this study, we investigated the preventive potential of chamomile (Matricaria chamomilla L.) towards cancer by focusing on its anti-inflammatory activity. METHODS AND RESULTS: A virtual drug screening of 212 phytochemicals from chamomile revealed ß-amyrin, ß-eudesmol, ß-sitosterol, apigenin, daucosterol, and myricetin as potent NF-κB inhibitors. The in silico results were verified through microscale thermophoresis, reporter cell line experiments, and flow cytometric determination of reactive oxygen species and mitochondrial membrane potential. An oncobiogram generated through comparison of 91 anticancer agents with known modes of action using the NCI tumor cell line panel revealed significant relationships of cytotoxic chamomile compounds, lupeol, and quercetin to microtubule inhibitors. This hypothesis was verified by confocal microscopy using α-tubulin-GFP-transfected U2OS cells and molecular docking of lupeol and quercetin to tubulins. Both compounds induced G2/M cell cycle arrest and necrosis rather than apoptosis. Interestingly, lupeol and quercetin were not involved in major mechanisms of resistance to established anticancer drugs (ABC transporters, TP53, or EGFR). Performing hierarchical cluster analyses of proteomic expression data of the NCI cell line panel identified two sets of 40 proteins determining sensitivity and resistance to lupeol and quercetin, further pointing to the multi-specific nature of chamomile compounds. Furthermore, lupeol, quercetin, and ß-amyrin inhibited the mRNA expression of the proinflammatory cytokines IL-1ß and IL6 in NF-κB reporter cells (HEK-Blue Null1). Moreover, Kaplan-Meier-based survival analyses with NF-κB as the target protein of these compounds were performed by mining the TCGA-based KM-Plotter repository with 7489 cancer patients. Renal clear cell carcinomas (grade 3, low mutational rate, low neoantigen load) were significantly associated with shorter survival of patients, indicating that these subgroups of tumors might benefit from NF-κB inhibition by chamomile compounds. CONCLUSION: This study revealed the potential of chamomile, positioning it as a promising preventive agent against inflammation and cancer. Further research and clinical studies are recommended.

Impact of Cognitive Rehabilitation on Cognitive and Functional Outcomes in Adult Cancer Survivors: A Systematic Review.

OBJECTIVES: This systematic review (PROSPERO CRD42021275421) synthesized evidence on the efficacy of cognitive rehabilitation on cognitive and functional outcomes in adult cancer survivors. METHODS: Articles were identified though PubMed/MEDLINE, EMBASE, PsycINFO, and Web of Science from inception through June 30, 2023. Studies included participants ≥18 years old, diagnosed with cancer. Primary outcomes were validated measures of subjective and objective cognition. Articles were dual reviewed for eligibility and data extraction. Risk of bias was assessed with the Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields. RESULTS: The search yielded 3,811 articles; 65 full-text articles were reviewed; 53 articles (15 cognitive training, 14 strategy-based, 21 combinations, three inpatient rehabilitation), representing 52 unique studies, were included. Positive effects were observed in at least one objective cognitive measure in 93% of strategy training, 81% of cognitive training, 79% of combination rehabilitation interventions. Positive effects were observed in subjective cognition in 100% of strategy training, 55% of cognitive training, and 92% of combination interventions. Among studies with comparator groups, processing speed improved in 60% of cognitive training studies, while strategy training did not improve processing speed; otherwise, cognitive domain effects were similar between intervention types. Impact on functional outcomes was inconclusive. CONCLUSIONS: Cognitive rehabilitation appear beneficial for cancer-related cognitive impairment (CRCI). Differential effects on specific cognitive domains (eg, processing speed) and subjective cognition may exist between intervention types. IMPLICATIONS FOR NURSING PRACTICE: Nurses should increase patient and provider awareness of the benefits of cognitive rehabilitation for CRCI.

Patient-centric decision framework for treatment alterations in patients with Chemotherapy-induced Peripheral Neuropathy (CIPN).

Recently updated American Society of Clinical Oncology (ASCO) guidelines for Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN) in Survivors of Adult Cancers make a single recommendation to alter treatment by delaying, decreasing, or discontinuing dosing in patients who develop CIPN during neurotoxic chemotherapy treatment. Dosing guidelines have inconsistent recommendations for when (i.e., what CIPN severity) and how (i.e., delay, decrease, or discontinue) to alter neurotoxic chemotherapy treatment in patients with CIPN. Clinical decision making requires an understanding the benefits and risks of treatment alteration, in addition to consideration of other disease and patient factors. This review summarizes four areas of literature and culminates in a patient-centric decision framework to guide clinicians in helping patients to make treatment alteration decisions. First, we describe the current practice of altering treatment due to CIPN, including treatment alteration recommendations and published rates. Second, we summarize the potential benefits of treatment alteration including the reduction in CIPN severity and persistence. Third, we evaluate the potential risk of treatment alteration in compromising treatment efficacy by reviewing prospective trials comparing dosing regimens and retrospective analyses of the effect of relative dose intensity on efficacy. Fourth, we summarize disease and patient factors that should be considered when making a treatment alteration decision for a patient. We then propose a patient-centric decision framework that clinicians can use to assess an individual patient's current and anticipated future CIPN severity and compare that to their maximum tolerable severity to determine whether they should continue, delay, decrease, or discontinue neurotoxic chemotherapy.

The Incidence of Oxaliplatin-Induced Peripheral Neurotoxicity at Khartoum Oncology Hospital: A Cross-Sectional Survey.

OBJECTIVE: Using oxaliplatin-based chemotherapy in the treatment of cancer patients can cause a unique form of acute and chronic peripheral neurotoxicities. This study mainly aims to assess the incidence of oxaliplatin-induced peripheral neuropathy (OXAIPN). METHODS: A cross-sectional study among 121 patients treated with oxaliplatin-based chemotherapy was conducted during the period of January to April 2019 at Khartoum Oncology Hospital. The incidence of acute neurotoxicity was assessed using a descriptive questionnaire for most common hyperexcitability and transient symptoms, while the incidence of chronic neurotoxicity was measured by the 20-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy and graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.03. RESULTS: Acute and chronic OXAIPN were found in 49.6% and 41.3% of patients, respectively. Most of the patients who developed acute OXAIPN symptoms manifested cold-induced pharyngolaryngeal dysesthesias (73.3%) or perioral paresthesias (71.7%). No significant association exists between the severity of chronic neurotoxicity and basic demographics. Most (79.1%) of the patients did not inform the doctors about their complaints, and 43.5% of those who informed doctors did not take any medication to manage OXAIPN. CONCLUSIONS: This study exhibits that oxaliplatin-based chemotherapy can cause symptoms of peripheral neurotoxicity in most of the patients with colorectal or gastric cancer in the form of acute neurotoxicity or chronic neurotoxicity.