Glioblastoma (GBM) remains a highly lethal malignancy characterized by profound treatment resistance and metabolic plasticity. While photodynamic therapy (PDT) and the mitochondrial complex I inhibitor carboxyamidotriazole orotate (CTO) have individually shown promise, their combined potential requires further exploration and optimization. This study systematically investigated the interaction between 5-aminolevulinic acid (5-ALA)-mediated PDT and CTO in U87 GBM models. Intriguingly, we discovered a sequence-dependent interaction under the tested treatment schedules: CTO pre-incubation before PDT resulted in attenuated PDT-induced cytotoxicity, possibly due to CTO-mediated suppression of reactive oxygen species (ROS) accumulation. In contrast, a sequential "PDT→CTO" regimen enhanced anti-tumor efficacy both in vitro and in vivo. Mechanistically, the sequential approach was associated with enhanced mitochondrial depolarization and reduced expression of glycolysis-related genes, suggesting a potential metabolic "dual-hit" involving disturbance of mitochondrial function and compensatory glycolytic adaptation. These results highlight treatment sequence as a critical determinant of PDT-CTO interaction and provide a basis for further preclinical investigation of PDT followed by metabolic intervention as a combination strategy with potential translational relevance.

Bladder cancer is the fifth most common cancer in the United States, causing approximately 17,000 deaths annually. Due to its vast genetic and molecular heterogeneity, presentation, prognosis, and therapeutic response vary greatly between individuals. To improve patient outcomes, there is a need for better drug-screening platforms. The genetic heterogeneity of bladder cancer often leads to chemotherapy resistance or low response rates. Moreover, chemotherapies are often contraindicated in patients with select comorbidities. Organoids offer a better option to replicate the tumor microenvironment than traditional 2D cell cultures, improving drug development and personalized therapy. In this study, we bioprinted gelatin-methacrylol (GelMA)-based organoids containing bladder cancer cell lines of different grades to model muscle-invasive bladder cancer. In the organoids, we observed distinct grade-dependent tumor proliferation and progression dynamics. Treatment with standard-of-care chemotherapies revealed a grade-dependent tumor response consistent with in vivo patient data, highlighting the suitability of these organoids for rapid, reliable drug testing. Lastly, we used the organoids to test LCI139, a novel small-molecule inhibitor of PI3K, CDK4/6, and CDK9 designed for the treatment of epithelial cancers, underscoring the potential of our model to evaluate the efficacy of newly developed drugs. The ability to quickly biofabricate reproducible bladder cancer organoids that are adaptable to different tumor grades represents a novel strategy to create an in vitro platform with strong potential to predict treatment outcomes of bladder cancer patients.

More than 20 years after the discovery of lunasin, a clear shift in lunasin research is observable-from an initial focus on its direct in vitro anticancer effects toward strategies aimed at improving its bioavailability and repositioning it as a potential adjunct in cancer therapy. Lunasin, a soy-derived bioactive peptide, has been extensively studied for its antineoplastic properties. However, its limited oral bioavailability restrains its efficacy in clinical trials. Therefore, recent research on lunasin points towards the possibility of using it as an adjunct in cancer treatment, rather than as a stand-alone nutraceutical in humans. In preclinical models, in vitro and in vivo, lunasin can enhance the effects of standard anticancer drugs in breast and colon cancers. Research suggests that lunasin can potentiate the effects of drugs, such as tamoxifen, aspirin, cisplatin, and oxaliplatin, by sensitizing cancer cells to apoptosis, modulating cell cycle progression, reducing metastatic potential, and attenuating drug-resistance pathways, including PI3K/Akt, FAK/MAPK1/NF-κB, and integrin-mediated signaling. In combination with those drugs, lunasin exerts significant anticancer effects at concentrations substantially lower than those proven as effective in monotherapy, suggesting a potential role in dose reduction in conventional agents and, subsequently, mitigation of their adverse effects. Although the enhanced effect of those combinations has been shown in preclinical models, there is a distinct lack of human clinical trials in this matter. Available evidence supports a promising concept of lunasin as a molecular "priming" agent that might complement cytotoxic therapies rather than replace them. This combination-oriented paradigm may represent a shift in lunasin research and offer a novel direction for the use of bioactive peptides in precision oncology; however, further studies exploring this possibility, including human clinical trials, are needed to elucidate lunasin's role in nutraceutical-assisted cancer therapy.

Vasculogenic mimicry (VM) is a non-endothelial mode of tumor vascularization in which aggressive cancer cells form vessel-like networks that support microcirculation, metastasis, and resistance to anti-angiogenic therapies. VM is particularly prominent in triple-negative breast cancer (TNBC), but its molecular regulators remain incompletely understood. Focal adhesion kinase (FAK) and its paralog, proline-rich tyrosine kinase 2 (Pyk2), are closely related non-receptor tyrosine kinases implicated in epithelial-to-mesenchymal transition (EMT), invasion, and metastasis in TNBC. However, their roles in VM have not been defined. Here we perform transcriptomic analysis of FAK and Pyk2 clinical expression patterns using TNMplot V2, DepMap, and patient cohort datasets to systematically dissect the distinct contributions of FAK and Pyk2 to VM in TNBC. Our in vitro tube formation assay shows that in TNBC cells, knockdown of FAK, but not Pyk2, results in failure to form robust 3D vessel-like networks in Matrigel. Similarly, overexpression of Pyk2, but not FAK, in TNBC cells results in poor vessel-like network formation. Consistent with these findings, analysis of two independent patient cohorts (TCGA-BRCA and METABRIC) revealed selective upregulation of FAK in TNBC, while Pyk2 was inversely associated with vasculogenic-mimicry-associated gene expression, supporting the opposing roles of the two kinases in patient tumors. Taken together, these findings establish that FAK and Pyk2 govern VM through non-redundant, kinase-specific, and functionally opposed mechanisms: FAK acting as a positive regulator of VM, and Pyk2 as a context dependent suppressor of VM at elevated levels. These results nominate FAK as a candidate target for suppressing VM-driven tumor perfusion in TNBC and suggest that dual FAK/Pyk2 inhibition warrants caution hypotheses that remain to be tested pharmacologically.

The mammalian sirtuins (SIRTs), consisting of seven members (SIRT 1-7), are NAD⁺-dependent histone deacetylases (HDACs). Similar to other classical NAD⁺-independent HDACs, SIRTs regulate a wide range of key biological processes by deacetylating both histone and non-histone proteins. By linking cellular metabolism to tissue homeostasis, SIRTs play important roles in physiological regulation and are often deregulated in many human diseases including diabetes, neurodegeneration and cancer, particularly sarcomas. Here, we reviewed the expression and roles of SIRTs, especially the most studied family member SIRT 1, across several types of human sarcomas, including both bone and soft tissues sarcomas. We also discussed the clinical relevance of SIRTs and the potential of their modulation as a therapeutic strategy in sarcomas.

Posterior pituitary and hypothalamic neuronal tumors are uncommon sellar and suprasellar neoplasms that can mimic pituitary neuroendocrine tumors clinically and radiologically. The 5th edition World Health Organization classifications (Endocrine and Neuroendocrine Tumors) reinforce a lineage-based framework that separates anterior pituitary tumors from posterior pituitary and hypothalamic neuronal lineages, which is particularly important in hormone-negative lesions and limited tissue samples. This narrative review provides a practical, pathology-centered approach to classification by integrating key anatomic and radiologic clues with histomorphology and targeted immunohistochemistry. We highlight the value and limitations of thyroid transcription factor 1, outline a stepwise workflow incorporating anterior pituitary transcription factors and neuronal differentiation markers, and discuss when vasopressin immunostaining is informative. We also summarize selected molecular insights and clinical management considerations relevant to surgical planning and follow-up.

Malignant tumors require substantial energy sources for proliferation, and dietary composition may influence colorectal carcinogenesis through metabolic and microbiome-related mechanisms. This study investigated the association of low-carbohydrate high-fat dietary patterns with macroscopic tumor burden, morphologic inflammatory cell infiltration, and gut microbiome alterations using an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of colitis-associated colorectal cancer. Male C57BL/6 mice received AOM followed by three cycles of DSS and were fed a standard diet (SD), high-carbohydrate diet (HCD), low-carbohydrate high-fat lard-based diet (HFL), or low-carbohydrate high-fat coconut oil-based diet (HFC). Body weight, colon length, splenic weight, macroscopic tumor formation, hematoxylin and eosin (H&E)-based inflammatory cell infiltration, and gut microbiome composition were analyzed. The HFL and HFC groups exhibited higher body weights and relatively preserved colon lengths compared with the SD and HCD groups. Tumor number and total tumor size were reduced in the HFL and HFC groups. Total lymphocyte-like inflammatory cell infiltration was not increased in the high-fat diet groups, whereas per-tumor values were interpreted cautiously because they are affected by tumor number. Gut microbiome analysis demonstrated altered microbial composition, increased alpha diversity, and distinct temporal microbial dynamics in the high-fat diet groups. Because the HFL and HFC diets simultaneously changed carbohydrate content, fat content, fat source, and caloric density, these findings should be interpreted as exploratory effects of low-carbohydrate high-fat dietary patterns rather than independent effects of carbohydrate restriction, total fat, or fat source.

Malignant gliomas are highly aggressive primary brain tumors for which the therapeutic efficacy of cisplatin is frequently limited by intrinsic or acquired drug resistance. Despite advances in adjuvant therapies, overcoming chemoresistance remains a major challenge in the treatment of these malignancies. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of non-protein-coding transcripts involved in gene regulation, play important roles in modulating treatment responses. Several lncRNAs, including differentiation antagonizing non-protein-coding RNA (DANCR), HOXD antisense growth-associated long non-coding RNA (HOXD-AS1), MEG3, MALAT1, and HOTAIR, have been implicated in pathways associated with glioma progression and therapeutic resistance. In particular, DANCR has been reported to promote cisplatin resistance in glioma cells through suppression of apoptosis and activation of pro-survival signaling pathways. This review summarizes current evidence regarding the roles of lncRNAs in cisplatin resistance, highlighting mechanisms such as regulation of drug transport, DNA damage repair, apoptosis, cancer stem-cell maintenance, and signaling pathways associated with treatment adaptation. We also discuss current limitations, challenges for clinical translation, and gaps in the existing evidence. A better understanding of lncRNA-mediated resistance mechanisms may facilitate the identification of novel therapeutic targets and inform future studies aimed at overcoming cisplatin resistance in malignant gliomas.

A 64-year-old Asian woman diagnosed with synchronous breast ductal carcinoma in situ (DCIS) and stage IV EGFR-mutated non-small cell carcinoma of the lung (NSCLC). A decision was made to defer management of the DCIS and initiate Osimertinib for lung cancer treatment, since this was a life-limiting diagnosis. At 9 months, restaging FDG-PET CT showed an interval response in the NSCLC and complete loss of FDG avidity at the biopsy-proven DCIS site. Breast MRI confirmed complete imaging resolution of the DCIS. The clinical resolution of breast DCIS during third-generation EGFR inhibitor therapy has not been previously reported in humans and highlights a potential role for the EGFR/HER2 (ERBB) pathway in pre-invasive breast cancer.

The bacterial and toxin methods of cancer treatment date back 130 years. This paradigm rests on nonspecific bacterial-toxin-generated immunotherapy. This high-risk oncology research is experiencing a renaissance of methods that are among the most effective yet. Glioblastomas and other resistant cancers are the modern touchpoint, because of remission history following sepsis. Spurred by recent research deaths, we discuss protocols IRBs should consider in live bacterial or synthetic immuno-stimulatory trials. Human systemic inflammatory response syndrome immunology is unique due to non-functioning SIGLEC-13 and 17, which control excessive Toll-like receptor 4 (TLR-4) signaling. This is not a technicality like human CD8+/CD4+ T cells. SIGLEC-13&17 consequences are profound; humans are ≈330-200,000 times more sensitive to LPS/endotoxin than mice and rats. This human TLR-4 difference also applies to gene therapy and should inform the results from any animal model, including non-human primates. Clinical TLR-4 stimulation takes two forms: bacterial infection and sterile TLR-4 stimulators, and treatments differ. The stereotactic injection of calculated amounts of adjuvants like endotoxin, venoms/components, or synthetic alternatives may be safer than live bacteria. Inadequate planning for risk elements, basic predictive models, and treatments will likely cause death.