Anticancer Drug Treatment Research Articles

Abstract 5196: Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells

Abstract Bladder cancer (BC) is one of the most prevalent genitourinary tumors worldwide, with approximately 573,000 new cases reported. Approximately 80% of BC patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC) with a high five-year survival rate, while the remaining 20% are diagnosed with muscle-invasive bladder cancer (MIBC). Although the surgical operation has been utilized to BC, patients with NMIBC frequently experience disease recurrence, of which about 20% progress to MIBC. However, the response rate of MIBC patients to gemcitabine treatment has been shown to be limited to less than 40% efficacy, and only a small number of patients have potential benefits.Chemotherapy resistance is an obstacle to cancer therapy and is considered a major cause of recurrence. Thus, understanding the mechanisms of chemoresistance is critical to improving the prognosis of patients. Here, we have established a stepwise gemcitabine-resistant T24 bladder cancer cell line to understand the molecular mechanisms of chemoresistance within cancer cells. The characteristics of the stepwise chemoresistance cell line were divided into 4 phases (parental, early, intermediate, and late phases). These four phase cells showed increasingly aggressive phenotypes in vitro and in vivo experiments with increasing phases and revealed the molecular properties of the biological process from parent cells to phased gemcitabine-resistant cell line (GRC). Taken together, through the analysis of gene expression profile data, we have characterized gene set of each phase indicating the response to anticancer drug treatment. Specifically, we identified a multigene signature (23-genes including GATA3, APOBEC3G, NT5E, MYC, STC1, FOXD1, SMAD9) and developed a chemoresistance score consisting of that could predict eventual responsiveness to gemcitabine treatment. We suggest that our findings improve prognosis by predicting to acquiring of chemotherapy resistance in bladder cancer patients. Citation Format: Jae-Jun Kim, Gi-Eun Yang, Tae Hwan Shin, Sun-Hee Leem. Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5196.

Visually evaluating drug efficacy in living cells using COF-based fluorescent nanoprobe via CHA amplified detection of miRNA and simultaneous apoptosis imaging

BackgroundsCancer is a highly fatal disease which is close relative of miRNA aberrant expression and apoptosis disorders. Elucidation of the therapeutic efficacy through investigating the changes in miRNA and apoptosis holds immense importance in advancing the development of miRNA-based precision therapy. However, it remains a challenge as how to visually evaluate the efficacy during protocol optimization of miRNA-based anticancer drugs at the cellular level. Therefore, exploring effective and noninvasive methods for real-time monitoring of therapeutic efficacy in living cells is of great significance. ResultsHerein, we reported a novel fluorescent nanoprobe COF–H1/H2-Peptide for visually evaluating drug efficacy in living cells through amplified imaging of low-abundant miRNA-221 with catalytic hairpin assembly (CHA) circle amplification, as well as simultaneous caspase-3 imaging. With strong stability and good biocompatibility, this newly fabricated amplified nanoprobe showed high sensitivity and specificity for the detection of miRNA-221 and caspase-3, and the limit of detection (LOD) of miRNA-221 was as low as 2.79 pM. The fluorescent imaging results showed that this amplified nanoprobe could not only detect caspase-3 in living cells, but also effectively detect low levels of miRNA-221 with increasing anticancer drug concentration and treatment time. The smart nanoprobe had effective performance for optimizing miRNA-based drug treatment schedules by dual-color fluorescence imaging. SignificanceThis nanoprobe combined CHA amplified detection of intracellular miRNA-221 and synchronous apoptosis imaging, with excellent sensitivity for the detection of cellular low-level miRNA, enabling the realization of real-time assessment of the efficacy of miRNA-based therapy in living cells. This work presents a promising approach for revealing the regulatory mechanisms between miRNAs and apoptosis in cancer occurrence, development, and treatment.

Integrated Electrochemical Aptasensor Array toward Monitoring Anticancer Drugs in Sweat.

In the realm of clinical practice, the concurrent utilization of anticancer medications can enhance their overall therapeutic efficacy. However, it is crucial to acknowledge that the interactions among these anticancer drugs can potentially yield detrimental consequences on their intended outcomes. Consequently, the assessment of both anticancer potency and potential toxic side effects is greatly refined when multiple anticancer drugs are simultaneously detected and evaluated. Here, we designed a wearable electrochemical aptasensor array for monitoring multiple anticancer drugs in sweat. The integrated sensor array consists of three working electrodes modified with three different aptamers (Apt1, Apt2, and Apt3), a Au counter electrode, and a Ag/AgCl reference electrode. Molecular docking simulations were performed to show the binding affinities between three anticancer drugs and their corresponding aptamers. Various eigenvalues were derived from the square-wave voltammetry electrochemical signals, and these data sets were subjected to rigorous analysis through multivariate data analysis techniques. This analytical approach demonstrated exceptional performance by achieving flawless 100% accuracy in the precise identification of nine anticancer drugs consistently at uniform concentrations. Furthermore, the integrated wearable sensor array exhibited impressive capabilities, correctly recognizing all nine anticancer drugs with 100% accuracy and successfully distinguishing between these drugs in artificial sweat samples. The proposed sensor array presents good stability for 15 days. Flexibility tests showed stable device performance after 500 twisting cycles. This innovative wearable sensing array represents a novel approach for achieving real-time monitoring and precise adjustment of drug dosages. It offers invaluable insights for tailoring the treatment of anticancer drugs to individual patients, predicting both drug efficacy and potential adverse reactions within the field of clinical medicine.

Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene.

Patients with cancer die from cardiac dysfunction second only to the disease itself. Cardiotoxicity caused by anticancer drugs has been emphasized as a possible cause; however, the details remain unclear. To investigate this mechanism, we treated rat cardiomyoblast H9c2 cells with sunitinib, lapatinib, 5-fluorouracil, and cisplatin to examine their effects. All anticancer drugs increased ROS, lipid peroxide, and iron (II) levels in the mitochondria and decreased glutathione peroxidase-4 levels and the GSH/GSSG ratio. Against this background, mitochondrial iron (II) accumulates through the unregulated expression of haem oxygenase-1 and ferrochelatase. Anticancer-drug-induced cell death was suppressed by N-acetylcysteine, deferoxamine, and ferrostatin, indicating ferroptosis. Anticancer drug treatment impairs mitochondrial DNA and inhibits oxidative phosphorylation in H9c2 cells. Similar results were observed in the hearts of cancer-free rats treated with anticancer drugs in vitro. In contrast, treatment with pterostilbene inhibited the induction of ferroptosis and rescued the energy restriction induced by anticancer drugs both in vitro and in vivo. These findings suggest that induction of ferroptosis and inhibition of oxidative phosphorylation are mechanisms by which anticancer drugs cause myocardial damage. As pterostilbene ameliorates these mechanisms, it is expected to have significant clinical applications.

Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy.

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1-mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.

Initial Efficacy of the COVID-19 mRNA Vaccine Booster and Subsequent Breakthrough Omicron Variant Infection in Patients with B-Cell Non-Hodgkin's Lymphoma: A Single-Center Cohort Study.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Prediction of anticancer drug resistance using a 3D microfluidic bladder cancer model combined with convolutional neural network-based image analysis.

Bladder cancer is the most common urological malignancy worldwide, and its high recurrence rate leads to poor survival outcomes. The effect of anticancer drug treatment varies significantly depending on individual patients and the extent of drug resistance. In this study, we developed a validation system based on an organ-on-a-chip integrated with artificial intelligence technologies to predict resistance to anticancer drugs in bladder cancer. As a proof-of-concept, we utilized the gemcitabine-resistant bladder cancer cell line T24 with four distinct levels of drug resistance (parental, early, intermediate, and late). These cells were co-cultured with endothelial cells in a 3D microfluidic chip. A dataset comprising 2,674 cell images from the chips was analyzed using a convolutional neural network (CNN) to distinguish the extent of drug resistance among the four cell groups. The CNN achieved 95.2% accuracy upon employing data augmentation and a step decay learning rate with an initial value of 0.001. The average diagnostic sensitivity and specificity were 90.5% and 96.8%, respectively, and all area under the curve (AUC) values were over 0.988. Our proposed method demonstrated excellent performance in accurately identifying the extent of drug resistance, which can assist in the prediction of drug responses and in determining the appropriate treatment for bladder cancer patients.

Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts

The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is affected by the tumor microenvironment (TME). In this study, to recapitulate the PDAC TME exvivo, we cocultured patient-derived PDAC cells with mesenchymal and vascular endothelial cells derived from human induced pluripotent stem cells (hiPSCs) to create a fused pancreatic cancer organoid (FPCO) in an air-liquid interface. FPCOs were further induced to resemble two distinct aspects of PDAC tissue. Quiescent FPCOs were drug resistant, likely because the TME consisted of abundant extracellular matrix proteins that were secreted from the various types of cancer-associated fibroblasts (CAFs) derived from hiPSCs. Proliferative FPCOs could re-proliferate after anticancer drug treatment, suggesting that this type of FPCO would be useful for studying PDAC recurrence. Thus, we generated PDAC organoids that recapitulate the heterogeneity of PDAC tissue and are a potential platform for screening anticancer drugs.

THU545 Growth Hormone Receptor Antagonist As A Novel Combination Therapy Against Triple Negative Breast Cancer

Abstract Disclosure: P. Mora-Criollo: None. R. Basu: None. J.J. Kopchick: None. Triple Negative breast (TNBC) cancer is classified based on the absence of ER-, PR-, and HER2- receptors and is associated with high metastatic potential. TNBC accounts for approximately 15-20% of new breast cancer diagnoses and is responsible for most breast cancer-related deaths. First-line treatment of anticancer drugs can be effective in 30-70% of patients with TNBC, but during treatment, more than half of the patients develop resistance and progress into metastatic disease. Previous studies have demonstrated the link between growth hormone receptor (GHR) expression and mammary carcinogenesis and established that GHR signaling promotes breast cancer development and progression. Conversely, inhibition of GHR expression has been shown to arrest tumor initiation and reduce metastasis of mammary carcinoma cells. Here we present the feasibility studies for employing GHR as a target for novel combination therapeutic approaches in TNBC. We performed retrospective analysis of GHR transcript expression and survival in TNBC patients, followed by experimental data in cellular models using combinations of Pegvisomant (an FDA-approved GHR antagonist) with chemotherapeutic agents, as a potential therapeutic option in TNBC. Survival probability plots from the TCGA dataset of 405 TNBC samples showed that patients expressing high levels of the GHR showed a significantly poor survival (27 months, p=0.038) compared to patients expressing low GHRs (40.37 months). Additionally, human breast cancer MDA-MB-453 cells, when treated with human (hGH)(2.5 nM) increased activation of JAK2, STAT5, SRC, ERK1/2, and AKT, associated with cancer progression. Importantly, treatment of the cells with Paclitaxel (1 nM) + (hGH)(2.5 nM) increased ABCG2 expression and the epithelial-to-mesenchymal transition (EMT) makers (SLUG, SNAIL, N-cad) associated with drug resistance and tumor progression. On the contrary, when cells were treated with Pegvisomant (500 nM) in combination with Paclitaxel + GH, a significant decrease in protein and RNA expression of ABCG2 as well as EMT markers was observed. Next, serum collected from GH antagonist (GHA) mice and WT as control, were used to treat PY8119 mouse cells in combination with Paclitaxel (1 nM) + bovine (bGH)(2.5 nM). Downregulation of protein and RNA expression levels of ABCG2 as well EMT makers in GHA serum treatment compared to WT was also found. This preliminary data shows that the GHR antagonist, Pegvisomant, in combination with anticancer drugs, can be effective in attacking drug resistance in TNBC. Key words: Pegvisomant, growth hormone receptor Presentation: Thursday, June 15, 2023

Measuring Melanoma Nanomechanical Properties in Relation to Metastatic Ability and Anti-Cancer Drug Treatment Using Scanning Ion Conductance Microscopy.

A cell's mechanical properties have been linked to cancer development, motility and metastasis and are therefore an attractive target as a universal, reliable cancer marker. For example, it has been widely published that cancer cells show a lower Young's modulus than their non-cancerous counterparts. Furthermore, the effect of anti-cancer drugs on cellular mechanics may offer a new insight into secondary mechanisms of action and drug efficiency. Scanning ion conductance microscopy (SICM) offers a nanoscale resolution, non-contact method of nanomechanical data acquisition. In this study, we used SICM to measure the nanomechanical properties of melanoma cell lines from different stages with increasing metastatic ability. Young's modulus changes following treatment with the anti-cancer drugs paclitaxel, cisplatin and dacarbazine were also measured, offering a novel perspective through the use of continuous scan mode SICM. We found that Young's modulus was inversely correlated to metastatic ability in melanoma cell lines from radial growth, vertical growth and metastatic phases. However, Young's modulus was found to be highly variable between cells and cell lines. For example, the highly metastatic cell line A375M was found to have a significantly higher Young's modulus, and this was attributed to a higher level of F-actin. Furthermore, our data following nanomechanical changes after 24 hour anti-cancer drug treatment showed that paclitaxel and cisplatin treatment significantly increased Young's modulus, attributed to an increase in microtubules. Treatment with dacarbazine saw a decrease in Young's modulus with a significantly lower F-actin corrected total cell fluorescence. Our data offer a new perspective on nanomechanical changes following drug treatment, which may be an overlooked effect. This work also highlights variations in cell nanomechanical properties between previous studies, cancer cell lines and cancer types and questions the usefulness of using nanomechanics as a diagnostic or prognostic tool.

Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells

Brain expressed X-linked gene 2 (BEX2) encoded protein was originally identified to promote transcription by interacting with several transcription factors in the DNA–binding complexes. Recently, BEX2 was found to be localized in cytosol and/or mitochondria and regulate apoptosis in cancer cells and tumor growth. However, the molecular mechanism underlying its roles in cancer cells remains unclear. Here, we report that crotonylated BEX2 plays an important role in inhibiting chemotherapeutic agent-induced apoptosis via enhancing mitophagy in human lung cancer cells. BEX2 promotes mitophagy by facilitating interaction between NDP52 and LC3B. Moreover, BEX2 crotonylation at K59 is critical in the BEX2-mediated mitophagy in lung cancer cells. The K59R mutation of BEX2 inhibits mitophagy by affecting the interaction of NDP52 and LC3B. BEX2 expression is elevated after anticancer drug treatment, and its overexpression inhibits chemotherapy-induced apoptosis. In addition, inhibition of BEX2-regulated mitophagy sensitizes tumor cells to apoptosis. Furthermore, BEX2 promotes tumor growth and inhibits apoptosis by regulating mitophagy in vivo. We also confirm that BEX2 is overexpressed in lung adenocarcinoma and is associated with poor prognosis in lymph node metastasis-free cancer. Therefore, combination treatment with pharmaceutical approaches targeting BEX2-induced mitophagy and anticancer drugs may represent a potential strategy for NSCLC therapy.

Real-World Evidence for the Safety and Effectiveness of Naldemedine in the Management of Opioid-Induced Constipation in Patients With Cancer Pain: Post-hoc Subgroup Analysis of Post-marketing Surveillance in Japan.

Opioid-induced constipation is common and greatly affects the quality of life but is often under-recognised and undertreated. This study aimed to investigate the safety and effectiveness of naldemedine for opioid-induced constipation with cancer pain according to specific subgroups of clinical interest. In this exploratory post-hoc subgroup analysis of post-marketing surveillance from Japan (UMIN: 000042851), data were investigated by the subgroups: age (≥75, <75 years), Eastern Cooperative Oncology Group performance status (PS 0-2, 3-4), constipation severity (mild, moderate, severe), brain metastasis (yes, no), anticancer drug treatment (yes, no), opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), and prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none). Enrolled patients (n = 1184) received naldemedine (0.2 mg once daily) orally for up to 12 weeks. Regarding safety endpoints, the incidence of adverse drug reactions, including diarrhoea, was determined within each subgroup. Regarding effectiveness endpoints, improvement rates in the frequency and condition of bowel movements were investigated by subgroups. The incidence of adverse drug reactions, including diarrhoea, among subgroups ranged from 7.74% to 16.08% (diarrhoea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population. Through week two to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively. Naldemedine was well tolerated and effective in patients with opioid-induced constipation and cancer pain regardless of the subgroups investigated.

Preservation of circadian rhythm in hepatocellular cancer

Circadian rhythms are controlled at the cellular level by a molecular clock consisting of several genes/proteins engaged in a transcription-translation-degradation feedback loop. These core clock proteins regulate thousands of tissue-specific genes. Regarding circadian control in neoplastic tissues, reports to date have demonstrated anomalous circadian function in tumor models and cultured tumor cells. We have extended these studies by analyzing circadian rhythmicity genome-wide in a mouse model of liver cancer, in which mice treated with diethylnitrosamine at 15days develop liver tumors by 6months. We injected tumor-bearing and control tumor-free mice with cisplatin every 2h over a 24-h cycle; 2h after each injection mice were sacrificed and gene expression was measured by XR-Seq (excision repair sequencing) assay. Rhythmic expression of several core clock genes was observed in both healthy liver and tumor, with clock genes in tumor exhibiting typically robust amplitudes and a modest phase advance. Interestingly, although normal hepatic cells and hepatoma cancer cells expressed a comparable number of genes with circadian rhythmicity (clock-controlled genes), there was only about 10% overlap between the rhythmic genes in normal and cancerous cells. "Rhythmic in tumor only" genes exhibited peak expression times mainly in daytime hours, in contrast to the more common pre-dawn and pre-dusk expression times seen in healthy livers. Differential expression of genes in tumors and healthy livers across time may present an opportunity for more efficient anticancer drug treatment as a function of treatment time.

Pharmacovigilance Study of Anticancer Drugs in a Tertiary Care Teaching Hospital in North India: A Retrospective Study.

Anticancer agents are responsible for a majority of adverse drug reactions (ADRs) in cancer patients. ADR reporting with anticancer drugs is very rare in India due to the lack of awareness and knowledge about the Pharmacovigilance Programme of India. Hence, this study was done to assess the pattern of ADRs with anticancer agents in cancer patients and to increase awareness about ADR monitoring among healthcare professionals. This is an observational, retrospectiveand non-interventional study conducted in an ADR monitoring centre (AMC) in Govt. Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, North India. Voluntarily reported ADR forms with anticancer drugs as suspected drugs over a period of seven years from January 2016 to December 2022 were analyzed. Various parameters were analyzed, which include demographic details of the patients, type of ADR, department reporting ADR and suspected drug. Causality assessment, severity assessment and preventability assessment were done according to the World Health Organization Uppsala Monitoring Centre (WHO-UMC) scale, modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively. The maximum numbers of ADRs were reported in the age group of 41-60 years (68.29%) and in females (59.75%). The maximum number of ADRs was reported with the use of taxanes (docetaxel and paclitaxel) (24.39%), targeted drugs (geftinib, imatinib, bortezomib, bevacizumab, rituximab and pazopanib) (24.39%) and platinum co-ordination complexes (cisplatin, oxaliplatin and carboplatin) (17.07%). Majority of the ADRs reported were shivering and ADRs on the skin. Majority of the ADRs were probable (64.70%), mild in nature (85.29%), definitely preventable (45.58%) and probably preventable (45.58%). ADR monitoring is needed to increase the outcome of anticancer drug treatment in cancer patients. The quality of treatment in cancer patients can be improved through the timely management of these ADRs. It is a need of the present era to inform healthcare professionals about the Pharmacovigilance Programme to increase the reporting of ADRs due to anticancer drugs.

Breast Cancers Secreting Sialyl-fibronectin Are Less Likely to Cause Epithelial-mesenchymal Transition and Have Good Prognoses.

Elevated blood fibronectin (FN) levels have been observed in various cancers; however, their significance is controversial. We measured sialyl-fibronectin (S-FN), a type of FN secreted by tumor cells in the blood, and investigated whether blood S-FN secretion is associated with cancer malignancy and recurrent metastases. We constructed an enzyme-linked immunosorbent assay (ELISA) system that recognizes S-FN as an antigen and measured the amount of S-FN secreted into the blood of 89 patients with breast tumors. The relationship between S-FN secretion and prognostic predictors was analyzed. Immunostaining was performed to identify the site of S-FN secretion in the breast tissue. Among the 82 patients, 21 (25.6%, 21/82) and 61 (74.4%, 61/82) were blood S-FN-positive and S-FN-negative, respectively. Regarding prognostic predictors, blood S-FN-positive and S-FN-negative patients showed significant difference in locoregional recurrence (p=0.026), remote metastases (p=0.049), and histological margins (p=0.001). Locoregional recurrence was associated with positive histological margins in S-FN-positive patients. However, remote metastases were associated with N-factor and histological classification (HC) in S-FN-negative patients. Furthermore, S-FN particles were detected in the cytoplasm of breast cancer cells through immunostaining. After the onset of recurrent metastases, two S-FN-positive and six S-FN-negative patients received anticancer drug treatment; however, further progression was observed in five S-FN-negative patients. S-FN-positive patients are less likely to develop distant metastases, have a better prognosis, and may be less resistant to therapeutic agents than S-FN-negative patients, which contain many epithelial-mesenchymal transition cells.

Osteoporosis Associated with Breast Cancer Treatments Based on Types of Hormonal Therapy: A Cross-Sectional Study Using Korean National Sample Data.

Background and Objectives: This study aimed to investigate osteoporosis-related treatments and the overall anticancer drug treatment tendencies, with a focus on selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), in Korean patients with breast cancer from 2010 to 2019. Materials and Methods: Data were obtained from the Health Insurance Review and Assessment Service. Patients with breast cancer (International Classification of Diseases, 10th Revision code: C50) as a principal diagnosis at least once from 2010 to 2019 were included. Those with osteoporosis (M80, M81, or M82) as a principal or sub-diagnosis or those who received osteoporosis treatment at least once were categorized as the osteoporosis-related treatment group, and others as the non-osteoporosis-related treatment group. The trends of drug prescriptions and treatment costs in patient groups were evaluated using descriptive statistics. Results: Among all included patients, those aged 45-54 years (40.20%) without osteoporosis treatment and those aged 55-64 years (34.11%) with osteoporosis treatment were the most common. SERM was the most commonly prescribed anticancer drug (29.20%) in the entire patient group, followed by AIs (20.83%). Patients without osteoporosis treatment had the highest prescription rate of SERM (31.48%), and those with osteoporosis treatment had a higher prescription rate of AIs (34.28%). Additionally, SERM and AIs were prescribed most frequently before and after the age of 55 years, respectively, regardless of the presence of treatment. Conclusions: This study found that osteoporosis-related treatment and patient age were associated with anticancer drug prescriptions. The present findings would help clinicians and researchers in the clinical diagnosis and treatment of breast cancer.

Doxorubicin Changes the Spatial Organization of the Genome around Active Promoters.

In this study, we delve into the impact of genotoxic anticancer drug treatment on the chromatin structure of human cells, with a particular focus on the effects of doxorubicin. Using Hi-C, ChIP-seq, and RNA-seq, we explore the changes in chromatin architecture brought about by doxorubicin and ICRF193. Our results indicate that physiologically relevant doses of doxorubicin lead to a local reduction in Hi-C interactions in certain genomic regions that contain active promoters, with changes in chromatin architecture occurring independently of Top2 inhibition, cell cycle arrest, and differential gene expression. Inside the regions with decreased interactions, we detected redistribution of RAD21 around the peaks of H3K27 acetylation. Our study also revealed a common structural pattern in the regions with altered architecture, characterized by two large domains separated from each other. Additionally, doxorubicin was found to increase CTCF binding in H3K27 acetylated regions. Furthermore, we discovered that Top2-dependent chemotherapy causes changes in the distance decay of Hi-C contacts, which are driven by direct and indirect inhibitors. Our proposed model suggests that doxorubicin-induced DSBs cause cohesin redistribution, which leads to increased insulation on actively transcribed TAD boundaries. Our findings underscore the significant impact of genotoxic anticancer treatment on the chromatin structure of the human genome.

Racial differences in longitudinal toxicities of anticancer agents in early phase cancer clinical trials.

Racial differences have been reported in toxicity outcomes for anticancer drug treatments. However, these observations were often from studies with small sample sizes, and many only reported the maximum grade of toxicity and no longitudinal information. This current analysis aims to investigate racial differences in longitudinal toxicities using a large-scale clinical trials database. Early-phase clinical trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute, USA, that evaluated cytotoxic drugs and molecularly targeted agents between March 2000 and December 2012 were studied. Race was categorized as White, Black or African-American, and Asian. Each toxicity's grade prevalence, mean grade at each cycle, and time to develop grade 2 or higher toxicity was evaluated. In total, 25,442 patients from 697 trials were included in this study. The number of patients categorized as White, Black, and Asian designations was 22,756 (89%), 1874 (7%), and 812 (3%), respectively. Notable findings include the rate of any grade of diarrhea in Black people was 26% and 21% lower than that of White and Asian people. The median time to the first grade 2 or higher event was 6 cycles in White people, 8 in Black people, and 6 in Asian people. The rate of any grade hyperglycemia was significantly higher in Asian people. Although we identified several racial differences in longitudinal toxicities, most were of generally lower grade. Further study is needed to clarify the cause of racial differences in treatment-associated toxicities.

Why 3D in vitro cancer models are the future of cancer research?

Tumors are three-dimensional (3D) entities characterized by complex structural architecture which is necessary for adequate intercellular, intracellular and cell-to-matrix interactions among the aberrant cells in cancer. In the field of cancer research, 2D cell cultures are traditionally used for decades in the majority of experiments. The reasons for this are the vast benefits these models provide, including simplicity and cost effectiveness. However, it is now known that these models are exposed to much higher stiffness, they lose physiological extracellular matrix (ECM) on artificial plastic surfaces as well as differentiation, polarization and cell-cell communication. This leads to the loss of crucial cellular signaling pathways and changes in cell responses to stimuli when compared to in vivo conditions. Moreover, they cannot adequately mimic the complexity and dynamic interactions of the tumor microenvironment (TME) which is of great importance in anticancer drug treatments. 3D models seem more biomimetic compared to 2D cell monolayers because they offer the opportunity to model the cancer mass together with its environment which seems the key factor in promoting and directing cancer invasion. 3D cell culture with its additional dimensionality makes the difference in cellular responses because it influences the spatial and physical aspects of the cells in 3D culture. This affects the signal transduction and makes the behavior of 3D-cultured cells more physiologically relevant and reflective of in vivo cellular responses. This review focuses on major differences between 2D and 3D cell cultures, highlighting the importance of considering bioengineering humanized 3D cancer models as the future in cancer research. Additionally, it presents diverse 3D models currently used in cancer research, outlining their benefits and limitations. Precisely, this review highlights the differences between the 3D models with the focus on tumor stroma interactions, cell population and extracellular matrix composition providing methods and examples for each model from the studies done so far.

Carbon nanotube/poly-L-lysine hybrid-modified electrode as efficient platform for cell immobilization and electrochemical study

A facile and efficient electrochemical platform based on multi-walled carbon nanotube (MWCNT)-poly-L-lysine (PLL) hybrids was prepared for studying on the immobilization and in vitro electrochemical behavior of cells. The PLL/MWCNT hybrids form a reticulate structure on the electrode surface, which provides a biocompatible and efficient microenvironment for cell immobilization. In contrast to the cells/glass carbon (GC) electrode, the cells/PLL/MWCNT hybrid-modified GC electrode exhibits a negatively shifted peak potential and a greatly enhanced peak current, indicating better electrochemical property of the PLL/MWCNT for evaluating the electrochemical behavior of cells. The effect of anticancer drug (adriamycin, ADR) treatment on the electrochemical signal of human breast cancer MCF-7 cells was evaluated. The ADR treatment leads to obviously decrease of the cell voltammetric response, being well accordant with the results obtained from conventional in vitro cytotoxicity assay. The proposed method may provide a simple way to quantitatively study the in vitro cell viability and cytotoxicity of ADR or other anticancer drugs.