Cytotoxic Chemotherapy Research Articles

Break-induced replication drives large-scale genomic amplifications in cancer cells.

DNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies 1-3 . Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection 4-11 . Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR.

Metabolite-based inter-kingdom communication controls intestinal tissue recovery following chemotherapeutic injury

Cytotoxic chemotherapies have devastating side effects, particularly within the gastrointestinal tract. Gastrointestinal toxicity includes the death and damage of the epithelium and an imbalance in the intestinal microbiota, otherwise known as dysbiosis. Whether dysbiosis is a direct contributor to tissue toxicity is a key area of focus. Here, from both mammalian and bacterial perspectives, we uncover an intestinal epithelial cell death-Enterobacteriaceae signaling axis that fuels dysbiosis. Specifically, our data demonstrate that chemotherapy-induced epithelial cell apoptosis and the purine-containing metabolites released from dying cells drive the inter-kingdom transcriptional re-wiring of the Enterobacteriaceae, including fundamental shifts in bacterial respiration and promotion of purine utilization-dependent expansion, which in turn delays the recovery of the intestinal tract. Inhibition of epithelial cell death or restriction of the Enterobacteriaceae to homeostatic levels reverses dysbiosis and improves intestinal recovery. These findings suggest that supportive therapies that maintain homeostatic levels of Enterobacteriaceae may be useful in resolving intestinal disease.

Decitabine-based treatment strategy improved the outcome of HSCT in JMML: a retrospective cohort study.

Pre-HSCT disease control, suboptimal long-term prognosis, and a high recurrence incidence (RI) continue to pose significant challenges for hematopoietic stem cell transplantation (HSCT) in juvenile myelomonocytic leukemia (JMML) patients. This retrospective cohort study assessed the effectiveness of a decitabine (DAC)-based protocol in JMML patients undergoing HSCT. The pre-HSCT treatment includes initial and bridging treatment. The efficacy of DAC monotherapy versus DAC combined with cytotoxic chemotherapy(C-DAC) as initial treatment was compared, followed by DAC plus FLAG (fludarabine, cytarabine, and GCSF) as bridging treatment. The HSCT regimens were based on DAC, fludarabine, and busulfan. Post-HSCT, low-dose DAC was used as maintenance therapy. The study endpoints focused on pretransplantation simplified clinical response and post-HSCT survival. There were 109 patients, including 45 receiving DAC monotherapy and 64 undergoing C-DAC treatment. 106 patients completed bridging treatment. All patients were administered planned HSCT regimens and post-HSCT treatment. The initial treatment resulted in 88.1% of patients achieving clinical remission without a significant difference between the DAC and C-DAC groups (p=0.769). Clinical remission rates significantly improved following bridging treatment (p=0.019). The 5-year overall survival, leukemia-free survival, and RI were 92.2%, 88.4%, and 8.0%, respectively. A poor clinical response to pre-HSCT treatment emerged as a risk factor for OS (hazard ratio: 9.8, 95% CI: 2.3-41.1, p=0.002). Implementing a DAC-based administration strategy throughout the pre-HSCT period, during HSCT regimens, and in post-HSCT maintenance significantly reduced relapse and improved survival in JMML patients. Both DAC monotherapy and the DAC plus FLAG protocol proved effective as pre-HSCT treatments.

Hepatitis B virus reactivation risk associated with immune checkpoint inhibitors in tumor treatment: a retrospective study.

Hepatitis B virus (HBV) reactivation is a recognized complication of cytotoxic chemotherapy in patients with chronic hepatitis B. However, the risk of HBV reactivation with immune checkpoint inhibitors (ICIs) remains uncertain due to their exclusion from clinical trials. This study aimed to assess the incidence of HBV reactivation in patients with cancer undergoing ICI therapy, exploring associated risk factors. This retrospective study included patients with cancer who tested positive for hepatitis B surface antigen (HBsAg). The primary endpoint was incidence of HBV reactivation, whereas the secondary endpoint was occurrence of hepatic adverse events during ICI therapy. Among the 162 eligible patients (median age 59years; 85.8% men), HBV reactivation occurred in 4.3% at a median of 13weeks post-treatment initiation. At baseline, HBV DNA was undetectable in 78 patients; 88 received antiviral prophylaxis, while 74 patients did not. Reactivation rates were 3.5% in HBsAg-positive and 10% in hepatitis B core antibody (HBcAb)-positive individuals, with an overall rate of 4.3%. These rates were 1.1% with prophylaxis and 8.1% without. Twenty-two patients had grade 3-4 hepatitis, and 25 tested HBsAg-negative but HBcAb-positive. No HBV-related fatalities occurred. The absence of antiviral treatment was a significant risk factor for HBV reactivation. Our study underscores the risk of HBV reactivation in patients with cancer undergoing ICI therapy, especially among those lacking antiviral prophylaxis. Regular HBV DNA testing and antiviral prophylaxis are crucial preventive measures for HBV reactivation. These findings emphasize the importance of monitoring HBV status in patients receiving ICIs.

Performance status improvement and advances in systemic treatment after brain metastases resection: a retrospective single-center cohort study of non-small cell lung cancer patients

BackgroundBrain metastasis (BrM) is prevalent among patients with NSCLC, and surgical resection of BrM constitutes a promising treatment strategy for local management and histopathological diagnosis, although it is offered for a select group of patients. Limited information exists concerning the improvement in performance status (PS) following BrM resection or the outcomes stratified by subsequent systemic therapy.MethodsWe conducted a retrospective single-center cohort study including NSCLC patients with surgically resected BrM and focused on the improvement in PS and subsequent therapy after BrM resection.Results71 patients were included, and the median overall survival was 18.3 months (95% confidence interval [95% CI]: 8.7, not reached). Patients with NSCLC who underwent surgical resection of BrM showed significant improvement in PS (18% and 39% showed ECOG PS of 0–1, before and after BrM resection, respectively [p = 0.006]), and patients with PS improvement were younger than those with PS unimprovement (median, 62 years versus 66 years; p = 0.041). Regarding subsequent systemic therapy after BrM resection, 21 patients (30%) received cytotoxic chemotherapy, 14 patients (20%) received tyrosine kinase inhibitors (TKIs), 3 patients (4%) received immune checkpoint inhibitors (ICIs), and 21 patients (30%) received no subsequent therapy. The survival outcomes of patients stratified by subsequent systemic treatments suggested the tendency that those who received TKI or ICI showed better survival outcomes, although a small number of patients hindered statistical comparisons.ConclusionsWe describe the outcomes of patients with NSCLC who underwent surgical resection of BrM, revealing that younger patients were more likely to anticipate improvement in PS, and patients who received TKI or ICI after BrM resection tended to exhibit a more preferable prognosis.

Targeting of mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive disease which currently has no effective therapeutic targets and prominent biomarkers. The Sperm Associated antigen 5 (SPAG5) is a mitotic spindle associated protein with oncogenic function in several human cancers. In TNBC, increased SPAG5 expression has been associated with tumor progression, chemoresistance, relapse, and poor clinical outcome. Here we show that high SPAG5 expression in TNBC is regulated by coordinated activity of YAP, mutant p53 and MYC. Depletion of YAP or mutant p53 proteins reduced SPAG5 expression and the recruitment of MYC onto SPAG5 promoter. Targeting of MYC also reduced SPAG5 expression and concomitantly tumorigenicity of TNBC cells. These effects of MYC targeting were synergized with cytotoxic chemotherapy and markedly reduced TNBC oncogenicity in SPAG5-expression dependent manner. These results suggest that mutant p53-MYC-SPAG5 expression can be considered as bona fide predictors of patient’s outcome, and reliable biomarkers for effective anticancer therapies.

Outcomes and Prognostic Factors of Patients with Unresectable or Metastatic Esophageal Squamous Cell Carcinoma Undergoing Immunotherapy- Versus Chemotherapy-Based Regimens: Systematic Review and Pooled Analyses.

Immunotherapy-based regimens (IMT) versus cytotoxic chemotherapy (CHT) improved overall survival (OS) of patients with unresectable or metastatic esophageal squamous cell carcinoma (mESCC), but the role of prognostic variables is unclear. The study aims to explore the interaction of prognostic factors with survival after IMT or CHT. A systematic review was performed to select trials comparing IMT and CHT regimens in mESCC patients. A meta-analysis of upfront IMT + CHT vs. CHT trials evaluated the overall effect size and heterogeneity between studies. In view of the expected differences between chemotherapy and immunotherapy on the survival curve, to better explore the effect of any prognostic variables on OS, before and after progression, the treatment arms were evaluated as independent cohorts, and ten baseline variables were extracted and assessed by linear regression. Fourteen trials were identified. Seven studies compared upfront CHT + IMT vs. CHT documenting longer OS for CHT + IMT (HR 0.69, CI 0.65-0.72), without heterogeneity (Q = 1.43, p value = 0.968) or differences in the most represented subgroups. Twenty-nine study cohorts were selected from the 14 trials. Median OS and PPS, but not PFS, were significantly increased after IMT compared with CHT. The analysis of baseline variables after CHT documented a favorable prognostic effect for advanced age (β = 0.768, p value = 0.016), involvement of 0-1 metastasis sites (β = 0.943, p value = 0.005), and absence of previous radiation therapy (β = - 0.939, p value = 0.006), while none of them influenced prognosis after IMT. The introduction of upfront IMT prolonged mESCC patients OS, mostly improving the outcomes of young patients, with multiple metastasis sites and without previous radiotherapy.

Strategies for successful dose optimization in oncology drug development: a practical guide

ABSTRACT Dose optimization is a critical challenge in drug development. Historically, dose determination in oncology has followed a divergent path from other non-oncology therapeutic areas due to the unique characteristics and requirements in Oncology. However, with the emergence of new drug modalities and mechanisms of drugs in oncology, such as immune therapies, radiopharmaceuticals, targeted therapies, cytostatic agents, and others, the dose-response relationship for efficacy and toxicity could be vastly varied compared to the cytotoxic chemotherapies. The doses below the MTD may demonstrate similar efficacy to the MTD with an improved tolerability profile, resembling what is commonly observed in non-oncology treatments. Hence, alternate strategies for dose optimization are required for new modalities in oncology drug development. This paper delves into the historical evolution of dose finding methods from non-oncology to oncology, highlighting examples and summarizing the underlying drivers of change. Subsequently, a practical framework and guidance are provided to illustrate how dose optimization can be incorporated into various stages of the development program. We provide the following general recommendations: 1) The objective for phase I is to identify a dose range rather than a single MTD dose for subsequent development to better characterize the safety and tolerability profile within the dose range. 2) At least two doses separable by PK are recommended for dose optimization in phase II. 3) Ideally, dose optimization should be performed before launching the confirmatory study. Nevertheless, innovative designs such as seamless II/III design can be implemented for dose selection and may accelerate the drug development program.

The Impact of Biliary Injury on the Recurrence of Biliary Cancer and Benign Disease after Liver Transplantation: Risk Factors and Mechanisms.

Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted.

Evaluation of the CCL17/CCL22-CCR4 axis in pediatrics with B-cell acute lymphoblastic leukemia before and after a chemotherapy course

AimsAcute lymphoblastic leukemia (ALL) is the most common type of pediatrics cancer. Chemokines exert different roles in leukemia process through leukocyte recruitment and regulation of disease severity. Due to the prominent roles of chemokine/receptor axes, this study aimed to measure the blood expression levels of CCR4 and their ligands in pediatrics with B-cell ALL (B-ALL). We also evaluated the impact of cytotoxic chemotherapy on this axis. Material and MethodThirty children suffering from B-ALL were included in the study and followed up for 30 days after completion of a chemotherapy course. The blood sampling was performed before and after chemotherapy. 30 healthy donors have also entered the study as control subjects. The mRNA expression of CCL17, CCL22 and CCR4 genes was determined by quantitative real-time PCR. The frequency of the peripheral blood mononuclear cells expressing CCR4 (CCR4 + PBMCs) was also evaluated by the flow cytometry method. Moreover, we evaluated the association of the CCL17/CCL22-CCR4 axis with some diagnostic, prognostic and predictive biomarkers in ALL patients. ResultsThere was overexpression of the CCL17/CCL22-CCR4 axis along with lactate dehydrogenase (LDH) in pediatrics with B-ALL compared to healthy controls. After induction of chemotherapy, the blood expression levels of the CCL17/CCL22-CCR4 axis have reached the levels of healthy controls. The findings for the blood expression levels of CCR4 were also confirmed using flow cytometry. ConclusionThe CCL17/CCL22-CCR4 axis can be used as a novel predictive and prognostic biomarker in B-ALL.

Oral minoxidil for late alopecia in cancer survivors.

Late alopecia, defined as incomplete hair regrowth > 6months following cytotoxic chemotherapy or > 6months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.

The unique metabolome of clear cell ovarian carcinoma.

Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype-specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high-grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC-specific alterations in metabolic pathways including serine biosynthesis and ROS-associated pathways that could serve as potential therapeutic targets. Our study provides the first in-depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype-specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Neutrophils exposed to a cholesterol metabolite secrete extracellular vesicles that promote epithelial-mesenchymal transition and stemness in breast cancer cells.

Small extracellular vesicles (sEVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME). Here, we investigate the mechanisms by which sEVs derived from neutrophils treated with the cholesterol metabolite, 27-hydroxycholesterol (27HC), influence breast cancer progression. sEVs released from 27HC treated neutrophils enhance epithelial-mesenchymal transition (EMT) and stem-like properties in breast cancer cells, resulting in loss of adherence, increased migratory capacity and resistance to cytotoxic chemotherapy. Decreased microRNAs (miRs) within the sEVs resulted in activation of the WNT/β-catenin signaling pathway in recipient cells and suggest that this may be a predominant pathway for stem-like phenotype and EMT. Our findings underscore a novel mechanism by which 27HC-modulated neutrophils contribute to breast cancer pathophysiology through EV-mediated intercellular communication, suggesting potential therapeutic targets in cancer treatment.

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, itis also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

Chemotherapy-induced acetylation of ACLY by NAT10 promotes its nuclear accumulation and acetyl-CoA production to drive chemoresistance in hepatocellular carcinoma

Chemotherapeutic efficacy is seriously impeded by chemoresistance in more than half of hepatocellular carcinoma (HCC) patients. However, the mechanisms involved in chemotherapy-induced upregulation of chemoresistant genes are not fully understood. Here, this study unravels a novel mechanism controlling nuclear acetyl-CoA production to activate the transcription of chemoresistant genes in HCC. NAT10 is upregulated in HCC tissues and its upregulation is correlated with poor prognosis of HCC patients. NAT10 is also upregulated in chemoresistant HCC cells. Targeting NAT10 increases the cytotoxicity of chemotherapy in HCC cells and mouse xenografts. Upon chemotherapy, NAT10 translocates from the nucleolus to the nucleus to activate the transcription of CYP2C9 and PIK3R1. Additionally, nuclear acetyl-CoA is specifically upregulated by NAT10. Mechanistically, NAT10 binds with ACLY in the nucleus and acetylates ACLY at K468 to counteract the SQSTM1-mediated degradation upon chemotherapy. ACLY K468-Ac specifically accumulates in the nucleus and increases nuclear acetyl-CoA production to activate the transcription of CYP2C9 and PIK3R1 through enhancing H3K27ac. Importantly, K468 is required for nuclear localization of ACLY. Significantly, ACLY K468-Ac is upregulated in HCC tissues, and ablation of ACLY K468-Ac sensitizes HCC cells and mouse xenografts to chemotherapy. Collectively, these findings identify NAT10 as a novel chemoresistant driver and the blockage of NAT10-mediated ACLY K468-Ac possesses the potential to attenuate HCC chemoresistance.

A review of cutaneous apocrine carcinoma: epidemiology, diagnosis, prognosis, and treatment options.

Cutaneous apocrine carcinoma is a rare skin cancer arising from apocrine sweat glands. Disease-specific treatments are required for cutaneous adnexal carcinomas due to their heterogeneous treatment responsiveness. This review reports on the epidemiology, diagnosis, pathological features, surgical management, and use of systemic therapies for cutaneous apocrine carcinoma. Diagnosing cutaneous apocrine carcinoma requires presenting with distinctive pathological features and excluding metastatic adenocarcinomas, particularly breast cancer. Clinical findings are essential to exclude metastatic adenocarcinomas, and immunohistochemistry can be used as an adjunctive tool to rule out other diseases. Wide local excision is the standard treatment for resectable cutaneous apocrine carcinomas. Prophylactic lymphadenectomy should be considered as a treatment option given the high incidence of lymph node metastasis. Generally, cutaneous apocrine carcinomas are resistant to chemotherapy and radiation therapy; however, adjuvant radiotherapy is recommended for high-risk patients. Radiation or systemic therapy is administered to patients with distant metastases or recurrence. The systemic therapeutic options include cytotoxic chemotherapy, hormonal therapy, targeted therapy, and immune checkpoint inhibitors. Given the lack of data on clinical prognosis and standardized treatments, further studies are needed to improve our understanding of cutaneous apocrine carcinomas.

Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.

Breast cancer patients may initially benefit from cytotoxic chemotherapy but experience treatment resistance and relapse. Chemoresistant breast cancer stem cells (BCSCs) play a pivotal role in cancer recurrence and metastasis, however, identification and eradication of BCSC population in patients are challenging. Here, an mRNA-based BCSC signature is developed using machine learning strategy to evaluate cancer stemness in primary breast cancer patient samples. Using the BCSC signature, a critical role of polyamine anabolism in the regulation of chemotherapy-induced BCSC enrichment, is elucidated. Mechanistically, two key polyamine anabolic enzymes, ODC1 and SRM, are directly activated by transcription factor HIF-1 in response to chemotherapy. Genetic inhibition of HIF-1-controlled polyamine anabolism blocks chemotherapy-induced BCSC enrichment in vitro and in xenograft mice. A novel specific HIF-1 inhibitor britannin is identified through a natural compound library screening, and demonstrate that coadministration of britannin efficiently inhibits chemotherapy-induced HIF-1 transcriptional activity, ODC1 and SRM expression, polyamine levels, and BCSC enrichment in vitro and in xenograft and autochthonous mouse models. The findings demonstrate the key role of polyamine anabolism in BCSC regulation and provide a new strategy for breast cancer treatment.

Evaluation of Hepatitis Serology Screening Frequency and Viral Reactivation in Patients Followed with Biological Therapy or Cytotoxic Chemotherapy

Objective: Our study aimed to evaluate the results of hepatitis B and C serology screening before biological therapy and chemotherapeutic treatments in internal medicine clinics (rheumatology, medical oncology, and gastroenterology) by comparing between departments and investigating the virus reactivation status. Material and Method: The study included 1147 patients aged 18 and over who were admitted to the medical oncology, rheumatology, and gastroenterology departments between 2019 and 2021 and received cytotoxic chemotherapy and biological treatment. HBsAg, Anti-HBs, Anti-HBc, and Anti-HCV data were used to screen for hepatitis. The departments were compared and evaluated based on the frequency of screening and reactivation. Results: Before undergoing chemotherapy or biological therapy, 77% of patients in oncology, 40% in rheumatology, and 43% in gastroenterology were fully screened for hepatitis. The rates of incomplete screening were 16%, 48%, and 52%, respectively, while 3%, 10%, and 4% were never screened. In total, reactivation was observed in twelve patients (1.0%), while no reactivation was observed in 1135 patients (99.0%). A statistically significant correlation was found between the departments and the presence of reactivation (p

Drug-loaded nanoparticles for cancer therapy: a high-throughput multicellular agent-based modeling study.

Interactions between biological systems and engineered nanomaterials have become an important area of study due to the application of nanomaterials in medicine. In particular, the application of nanomaterials for cancer diagnosis or treatment presents a challenging opportunity due to the complex biology of this disease spanning multiple time and spatial scales. A system-level analysis would benefit from mathematical modeling and computational simulation to explore the interactions between anticancer drug-loaded nanoparticles (NPs), cells, and tissues, and the associated parameters driving this system and a patient's overall response. Although a number of models have explored these interactions in the past, few have focused on simulating individual cell-NP interactions. This study develops a multicellular agent-based model of cancer nanotherapy that simulates NP internalization, drug release within the cell cytoplasm, "inheritance" of NPs by daughter cells at cell division, cell pharmacodynamic response to the intracellular drug, and overall drug effect on tumor dynamics. A large-scale parallel computational framework is used to investigate the impact of pharmacokinetic design parameters (NP internalization rate, NP decay rate, anticancer drug release rate) and therapeutic strategies (NP doses and injection frequency) on the tumor dynamics. In particular, through the exploration of NP "inheritance" at cell division, the results indicate that cancer treatment may be improved when NPs are inherited at cell division for cytotoxic chemotherapy. Moreover, smaller dosage of cytostatic chemotherapy may also improve inhibition of tumor growth when cell division is not completely inhibited. This work suggests that slow delivery by "heritable" NPs can drive new dimensions of nanotherapy design for more sustained therapeutic response.

TP53 mutations in urothelial carcinoma: not all one and the same†.

Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, et al reports that disruptive versus non-disruptive TP53 mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive TP53 tumour mutations had poor overall survival versus those with non-disruptive TP53 mutations or wild type TP53 but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8+ T-cell infiltration was seen in tumours with disruptive mutations. The impact of different TP53 mutations on prognosis and therapy choices appears to be tumour- and therapy-type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of TP53 mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of TP53 mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of TP53 mutations on other clinically important aspects of the tumour microenvironment, including cancer-associated fibroblasts. Furthermore, the impact of gain-of-function mutations in TP53 and other related genes signalling upstream or downstream of TP53 is of wide interest. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.