Prevalência de tabagismo e morbimortalidade por câncer de pulmão nos estados brasileiros / Smoking prevalence and lung cancer morbimortality in Brazilian states / Prevalencia del tabaquismo y morbimortalidad por cáncer de pulmón en los estados brasileños

Introdução: O câncer de pulmão é uma doença grave, sendo a segunda maior causa de morte em todo o mundo, entretanto, em alguns países desenvolvidos, tornou-se já a primeira causa de morte. Cerca de 90% dos casos de neoplasia pulmonares são causados pela inalação da fumaça do cigarro. Objetivo: Correlacionar a prevalência de tabagismo e morbimortalidade por câncer de pulmão nos estados brasileiros, além de demonstrar a associação destes com sexo e faixa etária. Métodos: Estudo de caráter ecológico acerca da prevalência de tabagismo e morbimortalidade por câncer de pulmão nos estados brasileiros, nos períodos de 2013 e 2019, dividida por sexo e faixa etária. Foram utilizados bancos de coleta de dados como o Tabnet e Pesquisa Nacional de Saúde. Resultados: As maiores taxas de mortalidade e internações hospitalares foram do público masculino, em 2013, com taxa de 2,7 e 10, respectivamente, e em 2019 com 3,3 e 11,9, respectivamente. Ademais, a maior prevalência de tabagismo foi encontrada nos homens; entretanto seu índice tem caído, enquanto a quantidade de mulheres tabagistas tem aumentado. A Região Sul demonstrou maiores números de mortalidade em ambos os períodos estudados, com taxas de 4,9 e 5,8 por 100 mil habitantes, e morbidade hospitalar com 19,9 e 23,5 por 100 mil habitantes. Já a Região Norte se configurou com as menores prevalências: em 2013 apresentou taxa de óbito por câncer de pulmão de 1,0 e morbidade hospitalar de 3,5/100 mil habitantes, em 2019 apresentou taxa de mortalidade de 4,6 e internações de 1,6/100 mil habitantes. Os coeficientes de correlação de morbidade hospitalar e prevalência de tabagismo foram R2=0,0628, r=0,251 e p=0,042, enquanto os de mortalidade e prevalência de tabagismo foram R2=0,0337, r=0,183 e p=0,140. Conclusões: Na presente pesquisa, pode-se inferir que houve associação positiva na comparação entre taxa de morbidade hospitalar e prevalência de tabagismo; em contrapartida, não foi possível observar associação positiva na correlação da taxa de mortalidade por câncer de pulmão e prevalência de tabagismo.

Introduction: Lung cancer is a serious disease, being the second leading cause of death worldwide. Moreover, in some developed countries, it has already become the leading cause of death. About 90% of lung cancer cases are caused by cigarette smoking. Objective: To correlate the prevalence of smoking and lung cancer morbidity and mortality in Brazilian states, and to demonstrate their association with sex and age group as well. Methods: An ecological study on the prevalence of smoking and lung cancer morbidity and mortality in Brazilian states between 2013 and 2019, divided by sex and age group. The data collection databases Tabnet and National Health Survey were used. Results: The highest rates of mortality and hospital admissions were among men, in 2013 with a rate of 2.7 and 10, respectively, and in 2019 with 3.3 and 11.9, respectively. In addition, the highest prevalence of smoking was found in men, but this rate has fallen, while the number of women smokers has increased. The South region showed higher mortality rates in both periods studied, with rates of 4.9 and 5.8 per 100,000 inhabitants, and hospital morbidity with 19.9 and 23.5 per 100,000 inhabitants. The North region had the lowest prevalence, where in 2013, it had a death rate from lung cancer of 1.0 and hospital morbidity of 3.5/100 thousand inhabitants, and where in 2019, it had a mortality rate of 4.6 and hospitalizations of 1.6/100 thousand inhabitants. The correlation coefficients for hospital morbidity and smoking prevalence were R2=0.0628, r=0.251 and p=0.042, while for mortality and smoking prevalence, these were R2=0.0337, r=0.183 and p=0.140. Conclusions: In the present study, it can be inferred that there was a positive association between hospital morbidity rate and prevalence of smoking, while it was not possible to observe a correlation between lung cancer mortality rate and prevalence of smoking.

Introducción: El cáncer de pulmón es una enfermedad grave, siendo la segunda causa de muerte en todo el mundo, sin embargo, en algunos países desarrollados, ya se ha convertido en la primera causa de muerte. Alrededor del 90% de los casos de neoplasias pulmonares están causados por la inhalación del humo del cigarrillo. Objetivo: Correlacionar la prevalencia de tabaquismo y la morbimortalidad por cáncer de pulmón en los estados brasileños, además de demostrar la asociación de estos con el género y el grupo de edad. Métodos: estudio ecológico sobre la prevalencia de tabaquismo y morbimortalidad por cáncer de pulmón en los estados brasileños, dentro de los períodos 2013 y 2019, divididos por sexo y grupo de edad. Se utilizaron bancos de recogida de datos como Tabnet y la Encuesta Nacional de Salud. Resultados: las mayores tasas de mortalidad e ingresos hospitalarios se dieron en el público masculino, en 2013 con una tasa de 2,7 y 10, respectivamente, y en 2019 con 3,3 y 11,9, respectivamente. Además, la mayor prevalencia del tabaquismo se encontró en los hombres, sin embargo, su tasa ha disminuido, mientras que la cantidad de mujeres fumadoras ha aumentado. La región Sur presentó cifras más altas de mortalidad en ambos periodos estudiados, con tasas de 4,9 y 5,8 por 100.000 habitantes, y de morbilidad hospitalaria con 19,9 y 23,5 por 100.000 habitantes. Mientras que la región Norte se configuró con las prevalencias más bajas, en 2013 presentó una tasa de mortalidad por cáncer de pulmón de 1,0 y una morbilidad hospitalaria de 3,5/100.000 habitantes, en 2019 presentó una tasa de mortalidad de 4,6 y hospitalizaciones de 1,6/100.000 habitantes. Los coeficientes de correlación para la morbilidad hospitalaria y la prevalencia del tabaquismo fueron R2=0,0628, r=0,251 y p=0,042, mientras que para la mortalidad y la prevalencia del tabaquismo fueron R2=0,0337, r=0,183 y p=0,140. Conclusiones: En la presente investigación se puede inferir que existe una asociación positiva en la comparación entre la tasa de morbilidad hospitalaria y la prevalencia de tabagismo, en contrapartida, no fue posible observar una asociación positiva en la correlación de la tasa de mortalidad por cáncer de pulmón y la prevalencia de tabagismo.

Evaluation of Cytotoxic effect of Moringa peregrina seeds on Oral Cancer, CAL 27, Cell Line and Red Blood Cells Hemolysis / Evaluación del efecto citotóxico de las semillas de Moringa peregrina en el cáncer oral, CAL 27, líneas celulares y hemólisis de glóbulos rojos

Background: Moringa peregrina Forssk is a well-known plant in ethnomedicine due to its widespread uses in various diseases like cough, wound healing, rhinitis, fever, and detoxification. The plant seeds contain compounds that are cytotoxic to many cancer cells. During the therapeutic use of plants via the oral route, some compounds present in the plants may be cytotoxic to normal cell lines and red blood cells. Objective: This study was the first report of investigation of the cytotoxic profile on oral cancer, CAL 27, cell line, and hemolytic activities on human erythrocytes of Moringa peregrina seeds ethanolic extract (MPSE). Methods: MPSE was screened for its cytotoxic effect against oral cancer, CAL 27, cell line using 3-(4, 5-dimethylthiazol-2-yl)-2, 5,-diphenyltetrazolium bromide (MTT) assay. The toxicity of MPSE on human erythrocytes was determined by in vitro hemolytic assay. Results: MPSE showed significant anti-proliferative activity against oral cancer, CAL 27 cell line at lower concentrations with half maximal inhibitory concentration (IC50) value of 21.03 µg/mL. At 1,000 µg/ml of MPSE, the maximum hemolysis was found to be 14.3% which is within safer limit. Conclusions: This study revealed a potential anti-oral cancer of MPSE and provided a baseline for its potential use in oral cancer treatment with minimum hemolytic effect on human RBCs.

La Moringa peregrina Forssk es una planta muy conocida en etnomedicina debido a sus usos generalizados en diversas enfermedades como la tos, la cicatrización de heridas, la rinitis, la fiebre y la desintoxicación. Las semillas de la planta contienen compuestos citotóxicos para muchas células cancerosas. Durante el uso terapéutico de las plantas por vía oral, algunos compuestos presentes en ellas pueden ser citotóxicos para las líneas celulares normales y los glóbulos rojos. Objetivo: Este estudio fue el primer informe de investigación del perfil citotóxico sobre el cáncer oral, CAL 27, línea celular, y las actividades hemolíticas en eritrocitos humanos del extracto etanólico de semillas de Moringa peregrina (MPSE). Métodos: Se examinó el efecto citotóxico del MPSE contra la línea celular de cáncer oral CAL 27 mediante el ensayo con bromuro de 3-(4, 5-dimetiltiazol-2-il)-2, 5,-difeniltetrazolio (MTT). La toxicidad del MPSE sobre los eritrocitos humanos se determinó mediante un ensayo hemolítico in vitro. Resultados: MPSE mostró una actividad antiproliferativa significativa contra el cáncer oral, línea celular CAL 27 a concentraciones más bajas con un valor de concentración inhibitoria media máxima (IC50) de 21,03 µg/mL. A 1.000 µg/ml de MPSE, la hemólisis máxima fue del 14,3%, lo que está dentro del límite de seguridad. Conclusiones: Este estudio reveló un potencial anticancerígeno oral de MPSE y proporcionó una base para su uso potencial en el tratamiento del cáncer oral con un efecto hemolítico mínimo en los glóbulos rojos humanos.

Enzyme Inhibitory and Anti-cancer Properties of Moringa peregrina / Propiedades inhibidoras Enzimáticas y Anticancerígenas de la Moringa peregrina

Background: Moringa peregrina is widely used in the traditional medicine of the Arabian Peninsula to treat various ailments, because it has many pharmacologically active components with several therapeutic effects. Objective: This study aimed to investigate the inhibitory effect of Moringaperegrina seed ethanolic extract (MPSE) against key enzymes involved in human pathologies, such as angiogenesis (thymidine phosphorylase), diabetes (α-glucosidase), and idiopathic intracranial hypertension (carbonic anhydrase). In addition, the anticancer properties were tested against the SH-SY5Y (human neuroblastoma). Results: MPSE extract significantly inhibited α-glucosidase, thymidine phosphorylase, and carbonic anhydrase with half-maximal inhibitory concentrations (IC50) values of 303.1 ± 1.3, 471.30 ± 0.3, and 271.30 ± 5.1 µg/mL, respectively. Furthermore, the antiproliferative effect of the MPSE was observed on the SH-SY5Y cancer cell line with IC50 values of 55.1 µg/mL. Conclusions: MPSE has interesting inhibitory capacities against key enzymes and human neuroblastoma cancer cell line.

Antecedentes: La Moringa peregrina se utiliza ampliamente en la medicina tradicional de la Península Arábiga para tratar diversas dolencias, ya que posee numerosos componentes farmacológicamente activos con varios efectos terapéuticos. Objetivo: Este estudio tenía como objetivo investigar el efecto inhibidor del extracto etanólico de semillas de Moringaperegrina (MPSE) frente a enzimas clave implicadas en patologías humanas, como la angiogénesis (timidina fosforilasa), la diabetes (α-glucosidasa) y la hipertensión intracraneal idiopática (anhidrasa carbónica). Además, se comprobaron las propiedades anticancerígenas frente al SH-SY5Y (neuroblastoma humano). Resultados: El extracto de MPSE inhibió significativamente la α-glucosidasa, la timidina fosforilasa y la anhidrasa carbónica con concentraciones inhibitorias semimáximas (IC50) de 303,1 ± 1,3, 471,30 ± 0,3 y 271,30 ± 5,1 µg/mL, respectivamente. Además, se observó el efecto antiproliferativo del MPSE en la línea celular del cáncer SH-SY5Y con valores de IC50 de 55,1 µg/mL. Conclusiones: MPSE posee interesantes capacidades inhibitorias frente a enzimas clave y línea celular de neuroblastoma canceroso humano.

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

Human epidermal growth factor receptor-2 expression and subsequent dynamic changes in patients with ovarian cancer.

Human epidermal growth factor receptor-2 (HER2)-targeting drugs are increasingly being incorporated into therapeutic paradigms for non-breast cancers, yet studies on HER2 expression in ovarian cancer (OC) are inadequate. Here, we studied the HER2 status and dynamic changes in OC by reviewing the records of patients who underwent HER2 testing at a single institution. Clinical parameters, including histology, BRCA status, and immunohistochemistry (IHC), were evaluated alongside HER2 expression, timing, and anatomical location. Among 200 patients, 28% and 6% exhibited expression scores of 2+ and 3+, respectively. HER2 3+ scores were observed in 23%, 11%, 9%, and 5% of mucinous, endometrioid, clear cell, and high-grade serous tumors, respectively, and were exclusively identified in BRCA-wildtype, mismatch repair-proficient, or PD-L1-low-expressing tumors. The TP53 mutation rate was low, whereas ARID1A, KRAS, and PIK3CA mutations were relatively more prevalent with HER2 scores of 2+ or 3+ than with 0 or 1+. Four of the five tumors with an HER2 3+ score exhibited ERBB2 amplification. Among 19 patients who underwent multiple time-lagged biopsies, 11 showed increased HER2 expression in subsequent biopsies. Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

Identification of fibronectin type III domain containing 3B as a potential prognostic and therapeutic target for pancreatic cancer: a preliminary analysis.

BACKGROUND: Fibronectin type III domain containing 3B (FNDC3B), a member of the fibronectin type III domain-containing protein family, has been indicated in various malignancies. However, the precise role of FNDC3B in the progression of pancreatic cancer (PC) still remains to be elucidated. METHODS: In this study, we integrated data from the National Center for Biotechnology Information, the Cancer Genome Atlas, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets to analyze FNDC3B expression and its association with various clinicopathological parameters. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, along with Gene Set Enrichment Analysis (GSEA), single sample Gene Set Enrichment Analysis (ssGSEA) and estimate analysis were recruited to delve into the biological function and immune infiltration based on FNDC3B expression. Additionally, the prognostic estimation was conducted using Cox analysis and Kaplan-Meier analysis. Subsequently, a nomogram was constructed according to the result of Cox analysis to enhance the prognostic ability of FNDC3B. Finally, the preliminary biological function of FNDC3B in PC cells was explored. RESULTS: The study demonstrated a significantly higher expression of FNDC3B in tumor tissues compared to normal pancreatic tissues, and this expression was significantly associated with various clinicopathological parameters. GSEA revealed the involvement of FNDC3B in biological processes and signaling pathways related to integrin signaling pathway and cell adhesion. Additionally, ssGSEA analysis indicated a positive correlation between FNDC3B expression and infiltration of Th2 cells and neutrophils, while showing a negative correlation with plasmacytoid dendritic cells and Th17 cells infiltration. Kaplan-Meier analysis further supported that high FNDC3B expression in PC patients was linked to shorter overall survival, disease-specific survival, and progression-free interval. However, although univariate analysis demonstrated a significant correlation between FNDC3B expression and prognosis in PC patients, this association did not hold true in multivariate analysis. Finally, our findings highlight the crucial role of FNDC3B expression in regulating proliferation, migration, and invasion abilities of PC cells. CONCLUSION: Despite limitations, the findings of this study underscored the potential of FNDC3B as a prognostic biomarker and its pivotal role in driving the progression of PC, particularly in orchestrating immune responses.

Depletion of proteasome subunit PSMD1 induces cancer cell death via protein ubiquitination and DNA damage, irrespective of p53 status.

Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.

GGT5 facilitates migration and invasion through the induction of epithelial-mesenchymal transformation in gastric cancer.

BACKGROUND: Gamma-glutamyltransferase 5 (GGT5), one of the two members in the GGT family (GGT1 and GGT5), plays a crucial role in oxidative regulation, inflammation promotion, and drug metabolism. Particularly in the tumorigenesis of various cancers, its significance has been recognized. Nevertheless, GGT5's role in gastric cancer (GC) remains ambiguous. This study delves into the function and prognostic significance of GGT5 in GC through a series of in vitro experiments. METHODS: Employing online bioinformatics analysis tools such as The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Kaplan-Meier plotter, and cBioPortal, we explored GGT5 characteristics and functions in GC. This encompassed aberrant expression, prognostic value, genomic alterations and mutations, immune cell infiltration, and associated signaling pathways. Immunohistochemistry was conducted to assess GGT5 expression in GC and adjacent normal tissues. Subsequently, univariate and multivariate logistic regression analyses were applied to investigate the associations between GGT5 and clinical characteristics. CCK8, wound healing, and migration assays were utilized to evaluate the impact of GGT5 on cell viability and migration. Additionally, Gene Set Enrichment Analysis (GSEA) and Western blot analysis were performed to scrutinize the activity of the epithelial-mesenchymal transformation (EMT) signaling pathway under GGT5 regulation. RESULTS: GGT5 exhibits upregulation in gastric cancer, with its overexpression significantly linked to histological differentiation in GC patients (P < 0.05). Multivariate analysis indicates that elevated GGT5 expression is an independent risk factor associated with poorer overall survival in gastric cancer patients (P < 0.05). In vitro experiments reveal that downregulation of GGT5 hampers the proliferation and migration of GC cell lines. Finally, GSEA using TCGA data highlights a significant correlation between GGT5 expression and genes associated with EMT, a finding further confirmed by Western blot analysis. CONCLUSIONS: GGT5 emerges as a promising prognostic biomarker and potential therapeutic target for GC.

Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study.

PURPOSE: The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity (TGV), aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in PLGG. METHODS: MIB-1 LI of a cohort of 172 nonependymal PLGGs were comprehensively characterized. Correlation to TGV, assessed by sequential MRI-based three-dimensional volumetry, and PFS was analyzed. RESULTS: Mean MIB-1 LI accounted for 2.7% (range: < 1-10) and showed a significant decrease to 1.5% at secondary surgery (p = .0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R2 = .55, p < .0001), while correlation to TGV remarkably decreased after incomplete resection (R2 = .08, p = .013). Log-rank test showed no association of MIB-1 LI and 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46%, p = .73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95%, p = .75). CONCLUSION: These data confirm a correlation of MIB-1 LI and radiologically detectable TGV in PLGG for the first time. Compared with preoperative TGV, a crucially decreasing correlation of MIB-1 LI and TGV after surgery may result in limited prognostic capability of MIB-1 LI in PLGG.

CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Perspective on quantitative phase imaging to improve precision cancer medicine.

Significance: Quantitative phase imaging (QPI) offers a label-free approach to non-invasively characterize cellular processes by exploiting their refractive index based intrinsic contrast. QPI captures this contrast by translating refractive index associated phase shifts into intensity-based quantifiable data with nanoscale sensitivity. It holds significant potential for advancing precision cancer medicine by providing quantitative characterization of the biophysical properties of cells and tissue in their natural states. Aim: This perspective aims to discuss the potential of QPI to increase our understanding of cancer development and its response to therapeutics. It also explores new developments in QPI methods towards advancing personalized cancer therapy and early detection. Approach: We begin by detailing the technical advancements of QPI, examining its implementations across transmission and reflection geometries and phase retrieval methods, both interferometric and non-interferometric. The focus then shifts to QPI's applications in cancer research, including dynamic cell mass imaging for drug response assessment, cancer risk stratification, and in-vivo tissue imaging. Results: QPI has emerged as a crucial tool in precision cancer medicine, offering insights into tumor biology and treatment efficacy. Its sensitivity to detecting nanoscale changes holds promise for enhancing cancer diagnostics, risk assessment, and prognostication. The future of QPI is envisioned in its integration with artificial intelligence, morpho-dynamics, and spatial biology, broadening its impact in cancer research. Conclusions: QPI presents significant potential in advancing precision cancer medicine and redefining our approach to cancer diagnosis, monitoring, and treatment. Future directions include harnessing high-throughput dynamic imaging, 3D QPI for realistic tumor models, and combining artificial intelligence with multi-omics data to extend QPI's capabilities. As a result, QPI stands at the forefront of cancer research and clinical application in cancer care.

STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. To address this challenge, we developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of dimeric-amidobenzimidazole (diABZI) STING agonists to hydrophilic polymer chains through an enzyme-responsive chemical linker. To synthesize a first-generation SAPCon, we designed a diABZI prodrug modified with a DBCO reactive handle a cathepsin B-cleavable spacer for intracellular drug release and conjugated this to pendant azide groups on a 100 kDa poly(dimethyla acrylamide-co-azide methacrylate) copolymer backbone to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites where they it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in tumor tissue compared to a free diABZI STING agonist. Consequently, SAPCon promoted an immunogenic tumor microenvironment, characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+ T cells, resulting in inhibition of tumor growth, prolonged survival, and increased response to anti-PD-1 immune checkpoint blockade in orthotopic models of breast cancer. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy.

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo.

CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer.

Purpose: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER+/HER2-) BC, the most abundant subtype, remains unknown. Methods: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. Results: Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER+/HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/ß-Catenin, Hedgehog, and Notchsignaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. Conclusion: CD133-high ER+/HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response.

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1's role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

pH-Triggered Transformable Peptide Nanocarriers Extend Drug Retention for Breast Cancer Combination Therapy.

Increasing the penetration and accumulation of antitumor drugs at the tumor site are crucial in chemotherapy. Smaller drug-loaded nanoparticles (NPs) typically exhibit increased tumor penetration and more effective permeation through the nuclear membrane, whereas larger drug-loaded NPs show extended retention at the tumor site. In addition, cancer stem cells (CSCs) have unlimited proliferative potential and are crucial for the onset, progression, and metastasis of cancer. Therefore, a drug-loaded amphiphilic peptide, DDP- and ATRA-loaded Pep1 (DA/Pep1), is designed that self-assembles into spherical NPs upon the encapsulation of cis-diamminedichloroplatinum (DDP) and all-trans retinoic acid (ATRA). In an acidic environment, DA/Pep1 transforms into aggregates containing sheet-like structures, which significantly increases drug accumulation at the tumor site, thereby increasing antitumor effects and inhibiting metastasis. Moreover, although DDP treatment can increase the number of CSCs present, ATRA can induce the differentiation of CSCs in breast cancer to increase the therapeutic effect of DDP. In conclusion, this peptide nanodelivery system that transforms in response to the acidic tumor microenvironment is an extremely promising nanoplatform that suggests a new idea for the combined treatment of tumors.

Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial.

PURPOSE: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations. PATIENTS AND METHODS: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. RESULTS: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4-18.3], while the placebo group had a PFS of 10.9 months (9.0-13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. CONCLUSIONS: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).

St. Jude Survivorship Portal: sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors.

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and 400 million genetic variants from over 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry.

A scoping review of racial, ethnic, socioeconomic, and geographic disparities in the outcomes of older adults with cancer.

INTRODUCTION: Cancer health disparities are widespread. Nevertheless, the disparities in outcomes among diverse survivors of cancer ages 65 years and older ("older") have not been systematically evaluated. METHODS: We conducted a scoping review of original research articles published between January 2016 and September 2023 and indexed in Medline (Ovid), Embase, Scopus, and CINAHL databases. We included studies evaluating racial, ethnic, socioeconomic disadvantaged, geographic, sexual and gender, and/or persons with disabilities disparities in treatment, survivorship, and mortality among older survivors of cancer. We excluded studies with no a priori aims related to a health disparity, review articles, conference proceedings, meeting abstracts, studies with unclear methodologies, and articles in which the disparity group was examined only as an analytic covariate. Two reviewers independently extracted data following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis reporting guidelines. RESULTS: After searching and removing duplicates, 2573 unique citations remained and after screening 59 articles met the inclusion criteria. Many investigated more than one health disparity, and most focused on racial and ethnic (n = 44) or socioeconomic (n = 25) disparities; only 10 studies described geographic disparities, and none evaluated disparities in persons with disabilities or due to sexual and gender identity. Research investigating disparities in outcomes among diverse older survivors of cancer is increasing gradually-68% of eligible articles were published between 2020 and 2023. Most studies focused on the treatment phase of care (n = 28) and mortality (n = 26), with 16 examined disparities in survivorship, symptoms, or quality of life. Most research was descriptive and lacked analyses of potential underlying mechanisms contributing to the reported disparities. CONCLUSION: Little research has evaluated the effect of strategies to reduce health disparities among older patients with cancer. This lack of evidence perpetuates cancer inequities and leaves the cancer care system ill equipped to address the unique needs of the rapidly growing and increasingly diverse older adult cancer population.

Current usage of pembrolizumab in triple negative breast cancer (TNBC).

INTRODUCTION: The use of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 pathway has changed the landscape in the treatment of triple negative breast cancer (TNBC). The ICI pembrolizumab in combination with chemotherapy now forms a standard of care for the treatment of advanced PD-L1 positive TNBC and as part of neoadjuvant therapy for high-risk early-stage disease. Evidence in this space is rapidly advancing. AREAS COVERED: This review aims to highlight the evolving role of immunotherapy in TNBC management and to discuss current challenges. The studies in this review were searched from PubMed and ClinicalTrials.gov. EXPERT OPINION: The KEYNOTE-522 trial demonstrated that the addition of peri-operative pembrolizumab to neoadjuvant chemotherapy improves patient outcomes in early-stage TNBC. However, critical questions remain including how to select which patients truly gain benefit from the addition of pembrolizumab; the optimal duration of therapy, and the optimal adjuvant therapy depending on pathologic response.