Primary lung carcinomas are extremely rare in childhood, resulting in limited knowledge of their biology and potential therapeutic targets.

Molecules driving the cancer process are frequently difficult to target with traditional small-molecule drugs. Small interfering RNAs (siRNAs) offer high specificity, but their clinical translation is hindered by inefficient delivery and rapid degradation. We previously identified DMBT1-derived cell-penetrating peptides (CPPs) that encapsulate siRNA and improve serum stability in vitro.

Individuals with Li-Fraumeni syndrome (LFS) are at risk of developing cancer in multiple organs and therefore require a multimodal screening program. We assessed the performance of annual whole-body noncontrast magnetic resonance imaging (WBMRI) in early cancer detection for individuals with LFS.

The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes.

Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers with no enduring therapies. Thyroid hormone receptor β (TRβ), a recognized tumor suppressor, modulates the transcriptome altering gene expression in numerous intracellular signaling pathways. Our recent studies revealed that TRβ agonism inhibits glycogen metabolism in ATC cells. Our goal in the present study was to delineate the molecular mechanisms by which TRβ regulates glycogen synthesis and breakdown. In ATC cells, activation of TRβ induced changes in expression of genes and proteins in glycogen signaling concordant with downregulation of cancer metabolism. The impact on the cancer cell metabolic phenotype was determined by glycogen levels, cell viability, and reactive oxygen species characterization. Our results revealed that TRβ activation differentially regulates glycogen signaling pathways reflective of the genetic landscape of the cells. This suggests TRβ can suppress tumor growth and progression through multiple steps in glycogen metabolism, giving it a unique and distinct role in fine-tuning the microenvironment of the cell as an internal sensor of the general environment of the cell. These studies reveal the potential of a synergistic effect of TRβ agonism and inhibition of glycogen metabolism in the treatment of aggressive dedifferentiated thyroid cancers.

BackgroundGastric cancer is the fifth most common malignancy and third leading cause of cancer death in China, with advanced-stage five-year survival below 20%. βIII-tubulin (TUBB3) is overexpressed in cancers but its role in gastric cancer remains unclear.MethodsTUBB3 expression was analyzed using TCGA data and clinical samples. Knockdown models assessed its effects on proliferation, migration, and invasion in vitro and in vivo.ResultsTUBB3 was significantly upregulated in gastric cancer tissues versus normal mucosa. High TUBB3 correlated with poorer disease-free and overall survival but not other clinicopathological features. Functionally, TUBB3 knockdown inhibited proliferation via G2/M arrest and reduced migration/invasion by disrupting invadopodia, without affecting apoptosis, EMT, or ECM degradation. In vivo, TUBB3 depletion suppressed tumor growth and metastasis. Mechanistically, TUBB3 promoted G2/M transition via p21/Cyclin B1 and enhanced invasiveness through Cortactin/JNK activation.ConclusionTUBB3 overexpression predicts poor prognosis in gastric cancer. It drives proliferation via cell cycle regulation and metastasis through invadopodia formation, suggesting its potential as a therapeutic target.

Recent advancements in the cellular and molecular understanding of cancer biology have significantly increased the probability of managing uncontrolled cancer cell proliferation. Advancements in combinational drug delivery at a minimal dose in tumor reduction are providing alternative therapeutic approaches in the clinical management of different cancer types over traditional anticancer treatment regimes. In contrast, an emerging paradigm in RNA interference (RNAi)-based therapeutics has been under study for a few decades to overcome the limitation of conventional cancer therapy by targeting cancer at its genetic and epigenetic levels. The intricate crosstalk among multifaceted signaling and effector pathways in cancer has long been recognized, and the adaptability of this network to evade single-target interventions using RNAi in cancer treatment is driving the advancement of combinational RNAi-based therapies. Therefore, researchers are exploring combinations of small interfering RNA (siRNA), microRNA (miRNA), and other small RNAs to silence multiple genes simultaneously, offering a potential solution to treat ever-evolving cancer by overcoming resistance mechanisms of cancer cells. This review endeavors to bring attention to the rationale of combinational cancer therapy using RNAi-based therapeutics for effective cancer treatment. Here, we provide a comprehensive analysis of multigene targets designed for blocking different tumor-associated cellular functions. Our systematic analysis of preclinical tumor inhibition studies shows that combinational RNAi therapy outperforms by reducing the average tumor volume to 22.85% compared to that of 54.75% when treated with single RNAi therapies. Finally, we highlight the challenges and future perspectives inherent in the formulation of combinational RNAi-based therapies. Overall, this review underscores the potential of combinational RNAi-based therapy and may serve as a reference for researchers in the selection of precise and efficient RNAi combinations, promoting ongoing advancements in cancer treatment.

Pancreatic neuroendocrine neoplasms (PanNENs) are characterized by significant clinical heterogeneity and limited therapeutic options, particularly in metastatic or recurrent cases. Identifying actionable molecular targets and biomarkers is essential for improving patient outcomes.

EZH2, a core component of PRC2 complex, silences global gene expression by tri-methylating histone H3K27. It remains an elusive question that EZH2 hyperexpression discords with its H3K27me3 activity of gene suppression in advanced prostate cancer. Here, we report a nascent RNA-dependent PHF19-YTHDC1 condensate capable of switching EZH2-mediated gene suppression to activation during prostate cancer progression. We found that the long isoform of PRC2 accessory subunit PHF19, PHF19L, was highly expressed in advanced prostate cancer that promoted the tumor progression and hormonal therapy resistance. Mechanistically, PHF19L was recruited to the m6A modified nascent RNA through YTHDC1 and formed a liquid-like YTHDC1-PHF19L condensate that pulled the EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and the activated expression of EZH2-repressed genes. Therefore, our study reveals a biomolecular condensate that modulates the switch from EZH2-mediated epigenetic gene silence to activation during the progression of prostate cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol.26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun.2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

For many families severely affected with breast cancer, no inherited causal allele has been detected in any tumor suppressor gene. In an effort to understand the genetics underlying breast cancer in these families, we evaluated 136 such families for coinheritance of breast cancer with each of 79 common variants reported as high-confidence "risk alleles" for breast cancer by meta-analyses of genome-wide association studies. Simulations based on allele frequencies and family structures revealed one (and only one) of these 79 variants to cosegregate with breast cancer in the families significantly more frequently than expected by chance. This variant (rs2046210) is located 180 kb proximal to ESR1, encoding the estrogen receptor alpha. Reporter assays in MCF7 cells revealed enhancement by the genomic segment at this site of activity of ESR1 promoters, but no difference in effect among alternative haplotypes. In contrast, the 600 kb genomic region including ESR1 and rs2046210 harbored 11 rare variants, each of which cosegregated with breast cancer in one or a few families. For 9 of these 11 variants, reporter assays indicated significant allele-specific effects on ESR1 promoters, with the breast-cancer-linked allele of each variant yielding higher promoter activity. At the site with the most striking effect, the breast-cancer-linked allele was associated with increased binding by transcription factor AP2-gamma TFAP2C in both MCF7 and T47D cells. These results demonstrate coinheritance with breast cancer of rare alleles that increase activity of ESR1 promoters, and suggest that rare ESR1 regulatory alleles may contribute to inherited predisposition to breast cancer.

Molecular reprogramming at the interface between malignant and non-malignant contributes to heterogeneity and metastasis across various cancers. The optic nerve metastasis serves as a significant prognostic indicator for mortality in retinoblastoma (RB). This study seeks to unveil the molecular underpinnings of this phenomenon.

Advances in the prognostication, monitoring, and treatment of both the acute and chronic leukemias have led to drastically improved outcomes over the past 2 decades. With the advent of targeted therapies, including antibodies such as blinatumomab and inotuzumab and small molecule inhibitors, such as the BCR::ABL1 tyrosine kinase inhibitors, Bruton tyrosine kinase inhibitors, and venetoclax, the treatment landscape of leukemia has drastically changed, improving survival outcomes while relying less on overall chemotherapy intensity in many leukemia types. This progress has allowed the categorization of more leukemia types as favorable (i.e., chronic lymphocytic leukemia, younger acute lymphoblastic leukemia [patients younger than 60 years], and Philadelphia chromosome-positive acute lymphoblastic leukemia) in addition to the traditional favorable subtypes of acute promyelocytic leukemia, core-binding factor acute myelocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia. Advancements in the treatment of TP53-mutated, MECOM-rearranged, and treated secondary AML are still needed to improve outcomes in these adverse risk groups. The authors also review the recent progress in the treatment of the acute and chronic leukemias.

This study investigates the association between the levels of two tRNA-derived fragments, tRF-17-79MP9PP and tRF-18-79MP9P04, and the pathophysiology of prostate cancer (PCa).

68Ga-DOTATATE binds to somatostatin receptors (SSTR) and is used for PET/CT imaging for diagnosing meningioma and guiding postoperative radiotherapy. However, the relationship between the clinicopathological characteristics and the imaging features of 68Ga-DOTATATE PET/CT in meningioma remains undetermined.

Despite the discoveries of new and promising therapeutics, effective treatments for advanced and metastatic thyroid cancer (THCA) are still lacking. Epithelial-to-mesenchymal transition (EMT) is crucial for developing an invasive phenotype in tumor cells and, therefore, a hallmark of metastatic disease. We here investigate the effect of EGF-like repeat and discoidin I-like domain-containing protein 3 (EDIL3) on EMT in THCA and the mechanism involved. THCA cells with EDIL3 knockdown were generated to analyze the effect on EMT, proliferation, migration, invasion, and angiogenesis. THCA cells with knockdown of EDIL3 had increased expression of E-cadherin and decreased expression of Vimentin and Slug, proliferation, migration, invasion, and angiogenesis. GLI-similar 2 (GLIS2) bound to the EDIL3 promoter to activate its expression. Knockdown of GLIS2 promoted the killing activity of CD8+ T cells, while overexpression of EDIL3 reversed phenotypic changes and suppressed the anti-tumor responses of T cells. Overexpression of EDIL3 also reversed the inhibitory effects of knocking down GLIS2 alone on tumor metastasis in BALB/c nude mice. Together, our results demonstrate that EDIL3 induced by GLIS2 inhibits the anti-tumor activity of CD8+ T cells and promotes EMT in THCA.

Glutamine' synthetase (GS) plays a central role in glutamine metabolism and has been implicated in the progression and treatment resistance of hepatocellular carcinoma (HCC). Although previous studies have explored GS in tumor metabolism, its role in modulating mitophagy and radiosensitivity in HCC cells remains unclear.

Chemoresistance is a significant issue in glioblastoma (GBM) treatment due to recurrence, poor survival and limited salvage options. Non-invasive biomarkers can identify early chemoresistance. These cohorts may benefit from initiating early chemotherapy or second-line drugs at an earlier timeline.

Uveal melanoma (UM) is the most common intraocular malignancy, with poor prognosis in metastatic cases and limited response to conventional therapies. Despite advances in genetic stratification, the immunological landscape of primary UM remains poorly understood.

Post cytotoxic myeloid neoplasms signify a heterogenous pool of poorly understood hematologic neoplasms with unfortunate survival and ineffective therapies. There is a lack of consensus on prognostic indicators, primarily due to the heterogenous disease spectrum encompassing different pathological, cytogenomic and original disease variables. This retrospective, single-center study over 10 years duration on MN-pCT cases diagnosed at NCCCR, a member of Hamad Medical Corporation. The study aimed to analyze clinicopathologic and cytogenomic characteristics, identify key prognostic predictors, and assess their impact on mortality through univariate and multivariate analyses. We identified 42 MN-pCT patients, noting a 31.7% prevalence of autoimmune diseases as primary condition, which is higher than previously reported. TP53 was the most frequently mutated gene, found in 28.6% of tested cases. Significant determinants of a shorter latency period included prior exposure to alkylating agents and TP53 positivity (by NGS or IHC) (P < 0.05). Younger patients (≤ 50 years) exhibited longer survival (P = 0.018). Poor prognostic markers included dyserythropoiesis (P = 0.045), MPO downregulation (P = 0.026), mutated TP53 (NGS/IHC) (P = 0.004), and failure to achieve CR (P = 0.002). Multivariate Cox regression identified both a latency period of ≥ 5 years and TP53 positivity (detected by either NGS or IHC) as statistically significant independent factors associated with reduced overall survival (P < 0.05). It is important to highlight that P53 mutation by NGS was a common parameter identified by the multivariate analysis that adversely impacted both MN-Pct survival and OS. This study stands as a significant contribution to our understanding of the clinicopathologic characteristics and prognostic predictors of MN-pCT in MENA region. It also underscores the existence of adverse prognostic factors, extending beyond the genetic influences and emphasizing the necessity of recognizing it as a distinct entity in the future classification systems.