Aggressive Tumor Research Articles

Pediatric pleuropulmonary blastoma: analysis of four cases

BackgroundPleuropulmonary Blastoma (PPB) is an extremely uncommon, highly aggressive tumor that arises from either the lungs or pleura. According to Dehner, PPB was classified into three groups: type I (cystic), type II (mixed), and type III (solid). Type I tends to occur more commonly in infants and has a more favorable prognosis compared to types II and III. This tumor is very rare in pediatric age group; hence, there is no consensus on the optimal treatment regimen for it to date. Type I tumors, which resemble congenital lung cysts, can eventually progress to more aggressive type II and type III tumors. This article aims to increase general awareness of this pathology, clinical presentation, and differential diagnosis in order to identify this rare entity early in its course. By presenting 4 such cases, we highlight that PPB can be missed early in diagnosis and it is important to be alert when putting this rare tumor in differential diagnosis of cystic lung lesions.MethodsA retrospective study was conducted between 2015 and 2020 involving patients who had a definitive diagnosis of PPB with emphasis on clinical presentation, preoperative imaging studies, intra-operative findings, pathological reports, ancillary treatment, and outcomes. All patients were followed up every 6 months to monitor local recurrence and distant metastasis by undergoing physical exam and non-contrast enhanced CT of the chest. The primary outcome is to identify the mortality and morbidity (recurrence and distant metastasis) of PPB for cases admitted in our institute.ResultsFour children were diagnosed with PPB during the study period. Clinically, patients presented with manifestations ranging from respiratory distress, fever to obstructive shock and radiologically, 2 cases were presented with mediastinal mass and the other 2 presented with pneumothorax. Regrettably, none of the cases were diagnosed pre-operatively. One lesion proved to be type I, 2 were type II and one was type III. All cases underwent chemotherapy using the combination of vincristine, Adriamycin and cyclophosphamide (VAC regimen). Recurrence was detected in a type II case, around 2 years after operation, and the other type II case developed brain metastasis that was discovered 3 years after operation. Type I case showed no local or distant metastasis.ConclusionA prompt preoperative diagnosis and workup of cases of PPB is crucial to enable optimal intervention intraoperatively and early postoperative treatment. Though it is uncommon, PPB should be considered in the differential diagnosis of cystic lung lesions.

Characterizing the Transformation and Diagnosis of Atypical Lipomatous Tumor to Dedifferentiated Liposarcoma: Single Institutional Outcomes.

Atypical lipomatous tumor (ALT) in the extremities is a locally aggressive adipocytic tumor with the potential risk of transformation into dedifferentiated liposarcoma (DDLS). Studies seldom differentiate whether DDLS was diagnosed on initial biopsy, final resected specimen, or subsequent recurrence. Our study seeks to characterize how and when patients received their ALT or DDLS diagnoses to better understand the relationship between the two neoplasms. We performed a retrospective review of patients diagnosed with ALT or DDLS of the extremities. Clinical characteristics, including the method of diagnosis of an ALT or DDLS, time between diagnoses, and tumor recurrence was recorded. Univariate/multivariate analysis was performed to identify risk factors. Forty-five patients were diagnosed with ALT after core needle biopsy (CNB) and 41 of them received marginal en bloc excision. Three (7.3%) of these patients had a heterogeneous tumor on final resection, pathology revealed both ALT and DDLS. Four patients (8.2%) were diagnosed with DDLS from CNB and received negative margin en bloc excision. One of these tumors was identified as heterogeneous ALT/DDLS after resection. Fifty-three patients received marginal en bloc resection without CNB after a benign lipomatous mass was suspected on CT/MRI. Among these, one (1.9%) had a tumor with a heterogeneous composition of both ALT and DDLS on pathology. There were 11 (11.7%) ALT recurrences and 1 (1.0%) DDLS recurrence after ALT resection. Obtaining a proper diagnosis whether ALT or DDLS is critical. Our cohort found that amongst those concerning lipomatous lesions biopsied, 7.84% will show biopsy proven DDLS. Additionally, 6.67% of the biopsies will be false negatives and show DDLS on final pathology. Furthermore, our local recurrence for ALT was 11.7% recurring as ALT and 1.0% recurring as DDLS.

Integrated bioinformatics analysis and experimental validation on malignant progression and immune cell infiltration of LTBP2 in gliomas

BackgroundGliomas are the highly aggressive brain tumor and also the most devastating human tumors. The latent TGF binding proteins (LTBP) had been found to be involved in malignant biological process and could be used as potent biomarkers in several solid tumors. While the role of LTBP family in human glioma remain to be elucidated.MethodsNormalized gene expression and corresponding clinical data of 2407 gliomas samples in public datasets were downloaded from Gliovis. Kaplan–Meier methods and Cox regression analysis was used for survival analyses.Western blot (WB) and Immunohistochemical (IHC) testing were employed to test LTBPs protein level in 154 gliomas samples. Correlation between LTBP2 expression and immune infiltration was evaluated by immunofluorescence (IF) and IHC in glioma tissues. CCK8 and flow cytometric analysis were used to detect the effect of LTBP2 on glioma cells. Orthotopic glioma- mouse models were utilized to evaluate effects in vivo.ResultsLTBP2 mRNA level was dramatically higher in glioma samples compared with non-tumor brain tissues in XENA-TCGA_GTEx, Gill and Gravendeel datasets (all P < 0.01), and its expression positively correlated with glioma WHO grade, IDH1/2 wildtype and mesenchymal subtypes. These results were confirmed by In-house cohort which was detected by WB and IHC. We found that gliomas patients with high LTBP2 level had shorter OS than those with low LTBP2 level. LTBP2 expression significantly associated with glioma immune score (Spearman r = 0.68, P < 0.01)) and strongly correlated with infiltration degreee of macrophages both in lower grade gliomas (LGG) and GBM. Knocking down LTBP2 obviously reduced proliferation and enhanced sensitivity to temozolomide in U87 and U251 cells. Nude mice with lower expression of LTBP2 had slower tumor growth, and accompanied by less tumor-associated macrophages (TAMs) infiltration detected by IHC staining in vivo. Finally, low LTBP2 expression glioma patients who received chemotherapy survived longer than patients with high LTBP2 expression.ConclusionLTBP2 could be used as a prognostic marker, and high LTBP2 expression related to abundant TAMs infiltration and with a worse response to chemotherapy.

Metastatic Intracranial Choriocarcinoma in the Absence of a Primary Lesion: A Case Report

AbstractIntracranial choriocarcinoma is a rare and aggressive neoplasm characterized by the proliferation of trophoblastic tissue. Although choriocarcinoma most commonly arises in the uterus as a component of gestational trophoblastic neoplasia, instances of intracranial choriocarcinoma are exceptionally uncommon. We report a case of intracranial choriocarcinoma without any evidence of a tumor elsewhere. A 25-year-old woman presented with a history of 1 month of evolution with right frontal hemicranial headache, followed by visual disturbances, otalgia, and diplopia. On neurological examination, she was conscious, cooperative, and well-oriented; a grade 1 bilateral papilledema, left homonymous hemianopsia, and sixth cranial nerve paresis, with diplopia, were detected. Neuroimaging showed a right parieto-occipital lesion with features mimicking an atypical meningioma. After surgical resection, a diagnosis of choriocarcinoma was issued. Primary intracranial choriocarcinomas are typically located in the sellar and pineal regions. The occurrence of this tumor within the occipital lobe suggested metastasis; however, a primary tumor in the thoracic or abdominal organs was not observed and a delayed metastasis was considered. This case highlights the diagnostic challenges associated with intracranial choriocarcinoma.

Disparities in Testicular Cancer: A Review of the Literature.

Background: Testicular cancer is the most common malignancy diagnosed in adolescents and young adults, and evidence has emerged regarding disparities that affect different groups of patients. Methods: In this article, we conducted a thorough review of this area and summarized the existing literature. Results: Some of the pertinent findings from our review include poorer outcomes for various groups including the native Māori population of New Zealand, those who live in the United States-Mexico border region, those who live in Eastern Europe, those who are uninsured and those with poorer socioeconomic status, amongst others. In the United States specifically, there is significant evidence showing that racial/ethnic minorities, compared to white patients, tend to fare worse with later presentation at higher stages and worse survival rates. Hispanic patients in particular appear to have the potential for more aggressive tumor biology than other groups and are projected to have the highest incidence rates in the US by 2026. Conclusions: Overall, disparities exist in many aspects of testicular cancer and are striking in some instances, and further research is needed in this arena and in potential solutions.

Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma

BackgroundDiffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies.ResultsTowards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients.ConclusionThe compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.

Brain targeted biomimetic siRNA nanoparticles for drug resistance glioblastoma treatment

Glioblastoma multiforme (GBM), the most aggressive intracranial neoplasm, remains incurable at present, primarily due to drug resistance, which significantly contributes to elevated recurrence rates and dismal prognosis. Signal transducer and activator of transcription 3 (STAT3) is a critical gene closely associated with GBM drug resistance and the progression of GBM stem cells (GSCs), making it a promising therapeutic target. In this study, we developed cancer cell membrane-cloaked biomimetic nanoparticles to deliver STAT3 siRNA to reverse drug resistance in homologous GBM. These biomimetic nanoparticles leverage homotypic targeting, rapid endosome escape, and fast siRNA release, leading to efficient in vitro STAT3 knockdown in both temozolomide-resistant U251-TR cells and X01 GSCs. Moreover, benefited from the membrane functionalization, significant prolonged blood circulation, improved blood brain barrier (BBB) penetration and GBM tumor accumulation are achieved by these siRNA biomimetic nanoparticles. Importantly, these nanoparticles effectively inhibit tumor proliferation, significantly extending median survival time in orthotopic U251-TR (43.5 d versus 20 d for PBS control) and X01 GSC-bearing mouse xenografts (52 d versus 19.5 d for PBS control). Altogether, this biomimetic siRNA platform offers a promising strategy for gene therapy targeting drug-resistant GBM.

Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma.

Glioblastoma (GBM) represents the most aggressive primary brain tumor, and urgently requires effective treatments. Oncolytic adenovirus (OA) shows promise as a potential candidate for clinical antitumor therapy, including in the treatment of GBM. Nevertheless, the systemic delivery of OA continues to face challenges, leading to significantly compromised antitumor efficacy. In this study, we developed an innovative approach by encapsulating CXCL11-armed OA with tannic acid and Fe3+ (TA-Fe3+) to realize the systemic delivery of OA. The nanocarrier's ability to protect the OA from elimination by host immune response was evaluated in vitro and in vivo. We evaluated the antitumor effect and safety profile of OA@TA-Fe3+ in a GBM-bearing mice model. OA@TA-Fe3+ effectively safeguarded the virus from host immune clearance and extended its circulation in vivo. After targeting tumor sites, TA-Fe3+ could dissolve and release Fe3+ and OA. Fe3+-induced O2 production from H2O2 relieved the hypoxic state, and promoted OA replication, leading to a remarkable alteration of tumor immune microenvironment and enhancement in antitumor efficacy. Moreover, the systemic delivery of OA@TA-Fe3+ was safe without inflammation or organ damage. Our findings demonstrated the promising potential of systemically delivering the engineered OA for effective oncolytic virotherapy against GBM.

On-Site Visualization Assay for Tumor-Associated miRNAs: Using Ru@TiO2 as a Peroxidase-like Nanozyme.

Accurate diagnosis of highly aggressive and deadly tumors is essential for effective treatment and improved patient outcomes, and microRNAs (miRNAs) have emerged as crucial biomarkers for their roles in tumor initiation, progression, and metastasis. Herein, we present an on-site visualization colorimetric assay for tumor-associated miRNAs using ruthenium nanoparticle decorated titanium dioxide nanoribbon (Ru@TiO2) as a peroxidase-like (POD) nanozyme. Remarkably, the Ru@TiO2 nanozyme can catalyze the oxidation of chromogenic substrates through its POD-like activity, which is effectively inhibited by pyrophosphate generated during the rolling circle amplification process, thereby enabling miRNA detection through a visible colorimetric readout. This approach provides a highly sensitive and specificity assay for miRNAs in diluted human serum with a detection limit of 100 pM. It shows great potential for clinical diagnostics and biological research, offering a promising tool for early cancer diagnosis and molecular diagnostics.

Cancer Epithelial Cells Participate in the Self-Organization of Lung Tumor Spheroids: A Morphological Approach

Plain Language SummaryLung cancer remains a significant public health problem, causing millions of deaths each year, making it crucial to understand its complexities in order to developing effective therapeutic strategies. The tumor microenvironment, which refers to the environment surrounding a tumor and includes various cell types, signaling molecules, and the extracellular matrix, influences how the tumor grows and responds to treatments. This study investigates how different cells interact in lung cancer, using a 3D model that mimics cancer microenvironment. Spheroids of two types of lung cancer cells, H460 and H1792, with or without stromal cells were cultured in a collagen matrix, to study their behavior. The results showed that when cancer cell spheroids were cultured with stromal cells, the spheroids formed branches and the tumors grew larger. Gene expression analysis revealed that the cells were undergoing a process called EMT, associated with more aggressive tumor behavior. Detailed studies of cellular structure confirmed that stromal cells were causing significant changes in cancer cells. This model helps understand the progression of lung cancer and can be used to quickly test new drugs.

AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3-6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. OnceTNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

Plasma-derived extracellular vesicles miR-335–5p as potential diagnostic biomarkers for fusion-positive rhabdomyosarcoma

BackgroundRhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with embryonal (ERMS) and alveolar (ARMS) representing the two most common histological subtypes. ARMS shows poor prognosis, being often metastatic at diagnosis. Thus, the discovery of novel biomarkers predictive of tumor aggressiveness represents one of the most important challenges to overcome and may help the development of tailored therapies. In the last years, miRNAs carried in extracellular vesicles (EVs), small vesicles of endocytic origin, have emerged as ideal candidate biomarkers due to their stability in plasma and their tissue specificity.MethodsEVs miRNAs were isolated from plasma of 21 patients affected by RMS and 13 healthy childrens (HC). We performed a miRNA profile using the Serum/Plasma Focus microRNA PCR panels (Qiagen), and RT-qPCR for validation analysis. Statistically significant (p < 0.05) miRNAs were obtained by ANOVA test.ResultsWe identified nine EVs miRNAs (miR-483-5p, miR-132-3p, miR-766-3p, miR-454-3p miR-197-3p, miR-335-3p, miR-17-5p, miR-486-5p and miR-484) highly upregulated in RMS patients compared to HCs. Interestingly, 4 miRNAs (miR-335-5p, miR-17-5p, miR-486-5p and miR-484) were significantly upregulated in ARMS samples compared to ERMS. In the validation analysis performed in a larger group of patients only three miRNAs (miR-483-5p, miR-335-5p and miR-484) were differentially significantly expressed in RMS patients compared to HC. Among these, mir-335-5p was significant also when compared ARMS to ERMS patients. MiR-335-5p was upregulated in RMS tumor tissues respect to normal tissues (p = 0.00202) and upregulated significantly between ARMS and ERMS (p = 0.04). Furthermore, the miRNA expression correlated with the Intergroup Rhabdomyosarcoma Study (IRS) grouping system, (p = 0.0234), and survival (OS, p = 0.044; PFS, p = 0.025). By performing in situ hybridization, we observed that miR-335-5p signal was exclusively in the cytoplasm of cancer cells.ConclusionWe identified miR-335-5p as significantly upregulated in plasma derived EVs and tumor tissue of patients affected by ARMS. Its expression correlates to stage and survival in patients. Future studies are needed to validate miR-335-5p as prognostic biomarker and to deeply elucidate its biological role.

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.

Elucidating the power of arginine restriction: taming type I interferon response in breast cancer via selective autophagy

BackgroundType I interferons (IFN-I) are potent alarm factors that initiate cancer cell elimination within tumors by the immune system. This critical immune response is often suppressed in aggressive tumors, thereby facilitating cancer immune escape and unfavorable patient outcome. The mechanisms underpinning IFN-I suppression in tumors are incompletely understood. Arginase-1 (ARG1)-expressing immune cells that infiltrate tumors can restrict arginine availability by ARG1-mediated arginine degradation. We hypothesized that arginine restriction suppresses the IFN-I response in tumors.MethodsComprehensive, unbiased open approach omics analyses, various in vitro techniques, including microscopy, qPCR, immunoblotting, knock-down experiments, and flow cytometry were employed, as well as ex vivo analysis of tumor tissue from mice. Several functional bioassays were utilized to assess metabolic functions and autophagy activity in cancer cells.ResultsArginine restriction potently induced expression of selective autophagy receptors, enhanced bulk and selective autophagy and strongly suppressed the IFN-I response in cancer cells in an autophagy-dependent manner.ConclusionOur study proposes a mechanism for how tumor-infiltrating immune cells can promote cancer immune escape by dampening the IFN-I response. We suggest ARG1 and autophagy as putative therapeutic targets to activate the IFN-I response in tumors.

Challenges and advances in glioblastoma targeted therapy: the promise of drug repurposing and biomarker exploration.

Glioblastoma remains the most prevalent and aggressive primary malignant brain tumor in adults, characterized by limited treatment options and a poor prognosis. Previous drug repurposing efforts have yielded only marginal survival benefits, particularly those involving inhibitors targeting receptor tyrosine kinase and cyclin-dependent kinase-retinoblastoma pathways. This limited efficacy is likely due to several critical challenges, including the tumor's molecular heterogeneity, the dynamic evolution of its genetic profile, and the restrictive nature of the blood-brain barrier that impedes effective drug delivery. Emerging diagnostic tools, such as circulating tumor DNA and extracellular vesicles, offer promising non-invasive methods for real-time tumor monitoring, potentially enabling the application of targeted therapies to more selected patient populations. Moreover, innovative drug delivery strategies, including focused ultrasound, implantable drug-delivery systems, and engineered nanoparticles, hold potential for enhancing the bioavailability and therapeutic efficacy of treatments.

Spinal Diffuse Midline Glioma H3 K27M-Altered: Report of a Rare Tumor with Extracranial Skeletal Metastases and Review of Literature.

Diffuse midline glioma, H3 K27-altered is a rare and aggressive pediatric brain tumor with a grim prognosis. Diffuse midline glioma is characterized by specific molecular alterations, including H3 K27 mutations, and involves deep midline structures such as the brainstem, cerebellum, spinal cord, and thalamus. These tumors present with a classic triad of symptoms and have limited surgical options due to their challenging locations. Extra-neural metastases are an unusual occurrence in diffuse midline glioma and have been rarely described. Here we report a 17-year-old girl with spinal diffuse midline glioma, H3 K27M-mutant, who presented with multiple metastatic osseous lesions confirmed on biopsy of the thoracic vertebral lesion. Due to the rapid disease progression, the patient was recommended palliative therapy. Extra-neural metastases in diffuse midline glioma are rare, with only 16 reported patients, and no standard therapy exists. An accurate and early diagnosis is necessary to develop a personalized plan of treatment. Further research is needed to gain insights into the molecular pathology of diffuse midline glioma, H3 K27-altered, and improve the quality of life and the outcome of patients with this deadly disease.

Tackling Anticancer Drug Resistance and Endosomal Escape in Aggressive Brain Tumors Using Bioelectronics.

Resistance mechanisms in brain tumors, such as medulloblastoma and glioblastoma, frequently involve the entrapment of chemotherapeutic agents within endosomes and the extracellular expulsion of drugs. These barriers to effective treatment are exacerbated in nanotechnology-based drug delivery systems, where therapeutic nanoparticles often remain confined within endosomes, thus diminishing their therapeutic efficacy. Addressing this challenge necessitates the development of novel strategies to enhance the efficiency of cancer therapies. This study tests the hypothesis that external electrical stimuli can modulate intracellular trafficking of chemotherapeutic drugs in common malignant brain tumors in children (medulloblastoma) and adults (glioblastoma) by using gold nanoparticles (GNPs). In our experiments, alternating current (AC) stimulation ranging from 1 kHz to 5 MHz and at a strength of 1 V/cm significantly reduced cell viability in drug-resistant medulloblastoma and enhanced delivery of GNPs in glioblastoma. Low-frequency AC resulted in a 50% increase in apoptosis compared to controls and an 8-fold increase in cell death in cisplatin-resistant medulloblastoma cells, accompanied by a substantial reduction in EC50 from 2.5 to 0.3 μM. Similarly, vincristine-resistant cells demonstrated a 4-fold enhancement in drug sensitivity. Furthermore, high-frequency AC facilitated a significant increase from 20 to 75% in the endosomal escape of GNPs in glioblastoma cells. These findings underscore the potential of AC to selectively disrupt cancer cell resistance mechanisms and bolster the efficacy of nanoparticle-based therapies. The results indicate the effectiveness of AC stimulation in circumventing the limitations inherent in current nanotechnology-based drug delivery systems but also illustrates its transformative potential for treating aggressive, drug-resistant brain tumors.

The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that requires novel treatment strategies, especially for relapsed/refractory cases. Dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, has been identified as a potential target for tumors. Besides, Teriflunomide (TRF) is a DHODH inhibitor with anticancer effects; however, its role in T-ALL remains poorly understood. Here, we investigated the potential anticancer effects of TRF on T-ALL cells, and the results showed that TRF inhibited cell proliferation, caused S-phase cell cycle arrest, and promoted apoptosis of T-ALL (MOLT4 and JURKAT) cell lines. In addition, TRF reduced the infiltration capacity of T-ALL cells in T-ALL xenograft mice while up-regulating the expression of P53 and BTG2. The BTG2 knockdown significantly attenuated the inhibitory effect of TRF on cellular growth and suppressed the TRF-mediated elevated expression of P53 in T-ALL cells. Moreover, combined treatment with TRF and daunorubicin (DNR) significantly reduced cell viability and promoted apoptosis in DNR-resistant T-ALL cells. Our study provides valuable insights into the critical role of TRF in treating T-ALL while increasing the sensitivity of DNR-resistant T-ALL cells to DNR.

Serum cyfra21-1 is a new prognostic biomarker of penile squamous cell carcinoma

ObjectiveOur study tried to evaluate the prognostic utility of preoperative serum cyfra21-1 in patients with penile squamous cell carcinoma (PSCC).MethodsThis retrospective study analyzed data from 94 patients who underwent either partial or radical penectomy accompanied by bilateral inguinal or pelvic lymphadenectomy at our institution from 2010 to 2018. The median duration of follow-up was 66.5 months. Serum cyfra21-1 concentrations were quantified through enzyme-linked immunosorbent assay, with patients classified into two groups based on cyfra21-1 levels (≤ 3.30 ng/ml and > 3.30 ng/ml). The impact of cyfra21-1 levels on clinical outcomes was evaluated.ResultsAmong the 94 patients, 68 (72.3%) had normal cyfra21-1 levels, while 26 (27.6%) exhibited elevated cyfra21-1 levels. During the follow-up period, 38 patients (40.4%) experienced relapse, and 35 patients (37.2%) died from PSCC. A significantly higher occurrence of advanced pathological grades was observed in the elevated cyfra21-1 group compared to the normal group (P = 0.029). Patients with elevated cyfra21-1 levels had significantly worse disease-free survival (DFS) and disease-specific survival (DSS) than those with normal levels (P < 0.001 and P < 0.001, respectively). In multivariate analysis, cyfra21-1 (HR: 3.938, 95% CI: 1.927–8.049, P < 0.001), lymph node involvement (HR: 8.277, 95% CI: 2.261–30.298, P = 0.001), pathological grade (HR: 2.789, 95% CI: 1.110–7.010, P = 0.029), and ECOG (Eastern Cooperative Oncology Group) performance status (HR: 1.751, 95% CI: 1.028–2.983, P = 0.039) were independent predictors of worse DFS. Similarly, CYFRA 21 − 1 (HR: 3.000, 95% CI: 1.462–6.156, P = 0.003), lymph node involvement (HR: 9.174, 95% CI: 2.010–41.862, P = 0.003), and ECOG performance status (HR: 1.856, 95% CI: 1.053–3.270, P = 0.032) were independent predictors of worse DSS.ConclusionsHigh preoperative serum cyfra21-1 levels correlate with greater tumor aggressiveness and represent a novel, effective, and convenient prognostic biomarker for PSCC.

Macrophages: Key Players in the Battle against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC’s aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.