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In general, tumor cells display a more glycolytic phenotype compared to the corresponding normal tissue. However, it is becoming increasingly clear that tumors are composed of a heterogeneous population of cells. Breast cancers are organized in a hierarchical manner, with the breast cancer stem cells (BCSCs) at the top of the hierarchy. Here, we investigate the metabolic phenotype of BCSCs and their differentiated progeny. In addition, we determine the effect of radiation on the metabolic state of these two cell populations. Luminal, basal, and claudin-low breast cancer cell lines were propagated as mammospheres enriched in BCSCs. Lactate production, glucose consumption, and ATP content were compared with differentiated cultures. A metabolic flux analyzer was used to determine the oxygen consumption, extracellular acidification rates, maximal mitochondria capacity, and mitochondrial proton leak. The effect of radiation treatment of the metabolic phenotype of each cell population was also determined. BCSCs consume more glucose, produce less lactate, and have higher ATP content compared to their differentiated progeny. BCSCs have higher maximum mitochondrial capacity and mitochondrial proton leak compared to their differentiated progeny. Radiation treatment enhances the higher energetic state of the BCSCs, while decreasing mitochondrial proton leak. Our study indicated that breast cancer cells are heterogeneous in their metabolic phenotypes and BCSCs reside in a distinct metabolic state compared to their differentiated progeny. BCSCs display a reliance on oxidative phosphorylation, while the more differentiated progeny displays a more glycolytic phenotype. Radiation treatment affects the metabolic state of BCSCs. We conclude that interfering with the metabolic requirements of BCSCs may prevent radiation-induced reprogramming of breast cancer cells during radiation therapy, thus improving treatment outcome.

Surgical management of head and neck cancer requires a careful balance between complete resection of malignancy and preservation of function. Surgeons must also determine whether to resect important cranial nerves that harbor perineural invasion (PNI), as sacrificing nerves can result in significant morbidity including facial paralysis. Our group has previously reported that Dynamic Optical Contrast Imaging (DOCI), a novel non-invasive imaging system, can determine margins between malignant and healthy tissues. Herein, we use an in vivo murine model to demonstrate that DOCI can accurately identify cancer margins and perineural invasion, concordant with companion histology. Eight C3H/HeJ male mice were injected subcutaneously into the bilateral flanks with SCCVIISF, a murine head and neck cancer cell line. DOCI imaging was performed prior to resection to determine margins. Both tumor and margins were sent for histologic sectioning. After validating that DOCI can delineate HNSCC margins, we investigated whether DOCI can identify PNI. In six C3H/HeJ male mice, the left sciatic nerve was injected with PBS and the right with SCCVIISF. After DOCI imaging, the sciatic nerves were harvested for histologic analysis. All DOCI images were acquired intraoperatively and in real-time (10 s per channel), with an operatively relevant wide field of view. DOCI values distinguishing cancer from adjacent healthy tissue types were statistically significant (P < 0.05). DOCI imaging was also able to detect perineural invasion with 100% accuracy compared to control (P < 0.05). DOCI allows for intraoperative, real-time visualization of malignant and healthy tissue margins and perineural invasion to help guide tumor resection.

Head and neck cancer is the sixth most common cancer in the world, with more than 300,000 deaths attributed to the disease annually. Aggressive surgical resection often with adjuvant chemoradiation is the cornerstone of treatment. However, the necessary chemoradiation treatment can result in collateral damage to adjacent vital structures causing a profound impact on quality of life. Here, we present a novel polymer of poly(lactic-co-glycolic) acid and polyvinyl alcohol that can serve as a versatile multidrug delivery platform as well as for detection on cross-sectional imaging while functioning as a fiduciary marker for postoperative radiotherapy and radiotherapeutic dosing. In a mouse xenograft model, the dual-layered polymer composed of calcium carbonate/thymoquinone was used for both polymer localization and narrow-field infusion of a natural therapeutic compound. A similar approach can be applied in the treatment of head and neck cancer patients, where immunotherapy and traditional chemotherapy can be delivered simultaneously with independent release kinetics.

Pigs have become important animal models in voice research. Several objective parameters exist to characterize the pig voice, but it is not clear which of them are sensitive to the impaired voice quality after laryngeal injury or surgery. In order to conduct meaningful voice research in pigs, it is critical to have standard functional voice outcome measures that can distinguish between normal and impaired voices. For this reason, we investigated 17 acoustic parameters before and early after surgery in three Yucatan mini pigs. Four parameters showed consistent changes between pre- and post-surgery recordings, mostly related to decreased spectral energy in higher frequencies after surgery. We recommend two of these, 50% spectral energy quartile (Q50) and Flux, for objective functional voice assessment of pigs undergoing laryngeal surgery. The long-term goal of this process is to enable quantitative voice outcome tracking of laryngeal surgical interventions in porcine models.

Objective Thymoquinone (TQ), the active constituent of Nigella sativa, has been shown to have anticancer effects in head and neck squamous cell carcinoma (HNSCC). This review aims to outline the properties of TQ, the known drivers in HNSCC formation, and summarize the anticancer effects of TQ in SCC. Data Sources Three databases (PubMed, Embase, and Google Scholar) were queried for the key words “thymoquinone squamous cell carcinoma.” Review Methods Publications that were not original research and publications that did not have full‐text available for review were excluded. Results Sixteen research articles met the inclusion criteria. Our review demonstrates that TQ‐induced cytotoxicity is associated with increased expression and activity of the tumor suppressor p53, proapoptotic proteins Bax and caspases, as well as decreased expression and activity of antiapoptotic proteins Bcl‐2 and Mdm2. Additionally, TQ modulates cell‐survival pathways such as the PI3k/Akt pathway. TQ synergizes with therapeutics including cisplatin and radiation. Early TQ administration may prevent carcinogenesis via upregulation of antioxidant enzymes, and TQ administration in the presence of cancer can result in disease mitigation via induction of oxidative stress. Conclusion TQ acts as an upregulator of proapoptotic pathways and downregulator of antiapoptotic pathways, modulates the oxidative stress balance in tumor development, and works synergistically alongside other chemotherapeutics to increase cytotoxicity. TQ has the potential to prevent carcinogenesis in patients who are at high‐risk for SCC and adjuvant treatment for SCC patients undergoing conventional treatments. Future studies should aim to identify specific populations in which TQ's effects would be the most beneficial. Level of Evidence Not available. Thymoquinone (TQ), the active constituent of Nigella sativa, has been shown to have anticancer effects in head and neck squamous cell carcinoma (HNSCC). Our review of TQ's effects in HNSCC demonstrates that TQ acts as an upregulator of proapoptotic pathways and downregulator of antiapoptotic pathways, modulates the oxidative stress balance in tumor development, and works synergistically alongside other chemotherapeutics to increase cytotoxicity. TQ has the potential to prevent carcinogenesis in patients who are at high‐risk for SCC and adjuvant treatment for SCC patients undergoing conventional treatments.

Objective This study aimed to assess if Nigella sativa oil (NSO), a health supplement containing thymoquinone as a major component, can act as a protective agent in salivary gland stem cells following radiotherapy (RT) damage. Methods Forty, 10‐week‐old, male C3H/HeJ mice were randomized to four experimental groups: sham RT + H2O gavage (control) (N = 4); 15 Gy RT + H2O gavage (N = 12); sham RT + NSO gavage (N = 12); and 15 Gy RT + NSO gavage (N = 12). Weight changes, saliva production, and salivary gland histopathologic staining were recorded for each group over the course of the experiment. Results All mice in the sham RT + H2O gavage and sham RT + NSO gavage groups demonstrated 100% 60‐day survival. RT + H2O compared to RT + NSO gavaged mice were significantly underweight by an average of 6.4 g (p < .001). Salivary output showed significant decline in RT + H2O gavaged mice at days 3 and 16, whereas salivary output in RT + NSO during these same time periods was comparable to the control. At day 60, all mice that survived recovered salivary function regardless of their treatment arm. Salivary specimens from the RT + NSO gavage group demonstrated early signs of recovery of Kr 5+ salivary gland stem cells in both submandibular and sublingual glands at day 16 with complete recovery by day 60, marked by strong histopathologic staining, whereas the RT + H2O gavage group did not recover as effectively. Conclusion NSO may help preserve salivary function in mice treated with RT and may mitigate xerostomia by accelerating the recovery of salivary gland stem cells. Level of evidence Not applicable. This study assessed if Nigella sativa oil (NSO), a health supplement containing thymoquinone, can protect salivary gland stem cells from radiation damage. Forty mice were randomized to four experimental groups, and weight changes, saliva production, and salivary gland histopathologic staining were recorded for each group over the course of the experiment. Results demonstrated that oral NSO may preserve salivary function in mice treated with radiotherapy and may prevent xerostomia (dry mouth) by accelerating the recovery of salivary gland stem cells.

Objective Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland malignancy. Herein, we present the largest single‐institution review of SDC to date. Methods This is a retrospective cohort study of all histologically confirmed cases of SDC seen at our institution from January 1, 2002, to August 1, 2022. Patient demographics, treatment, histological characteristics, tumor staging, and outcomes were extracted from the electronic medical record. Kaplan‐Meier and Cox regression survival analyses were performed. Results This study included 119 patients with a mean age of 66.2 years. Most primary tumors arose from the parotid gland (72.3%), and 23.5% were noted to be carcinoma ex‐pleomorphic adenoma. 57.1% of patients presented with regional lymph node metastasis, whereas 23.5% presented with distant disease. Kaplan–Meier analysis demonstrated a 62.4% 5‐year overall survival (OS) and a 69.0% 5‐year disease‐specific survival (DSS). Univariate analyses indicated that presence of regional lymph node disease (p<.001), distant metastasis (p<.001), perineural invasion (p = .027), and lymphovascular invasion (p = .018) were predictive of decreased OS and DSS. Trastuzumab administration was not associated with survival in HER‐2‐positive patients receiving chemotherapy. Multivariate analyses demonstrated that presence of nodal disease (HR 30.337, 95% CI 2.782–330.851, p = .005) and carcinoma ex pleomorphic adenoma (HR 5.54, 95% CI 1.024–29.933, p = .047) were associated with decreased OS. Conclusion Our patients had more favorable survival rates compared to prior studies, which may be due to lower incidence of nodal disease. Factors associated with worse survival included nodal and distant metastases, perineural invasion, lymphovascular invasion, and tumor size. Level of Evidence Level 3. Salivary duct carcinoma is a rare and aggressive malignancy, and survival data is limited. We have conducted the largest single‐institution study on SDC survival to date, which finds that nodal and distant metastases, perineural invasion, lymphovascular invasion, tumor size, and ex‐pleomorphic adenoma origin are associated with decreased survival.

Objectives Vocal fold (VF) scarring, manifested by increased collagen, decreased glycosaminoglycans (GAGs), and disrupted elastic fibers, remains a negative consequence of VF injury or resection. The objective of this study is to compare four reconstructive options after Vf mucosal resection in rabbits. A Cell‐Based Outer Vocal fold Replacement (COVR) using human adipose‐derived mesenchymal stromal cells (hASCs) in fibrin scaffold is directly compared with a decellularized scaffold implant, hASC injection, and resection alone without reconstruction. The primary hypothesis is that the cells‐in‐scaffold construct better reconstitutes the VF structure than either cells or scaffold alone, or than healing by secondary intention. Methods A total of49 rabbits received bilateral VF cordectomy, followed by either COVR implant, decellularized scaffold implant, hASC injection, or no reconstruction (injured control group). Larynges were harvested after 6 weeks. Results Histology demonstrated greater lamina propria thickness, less collagen deposition, and more GAGs in COVR animals versus all other treatment groups. Evidence of persistent human cells was found in about half of the cell‐treated animals. RNA levels of fibrosis pathway and macrophage phenotype markers were statistically unchanged among treatment groups at 6 weeks. Conclusion These data support the efficacy of COVR implantation in restoring VF microstructure in rabbits. The intact COVR was required; isolated components of decellularized scaffold or injected hASC still produced histologic scarring. We propose that the unique bilayered cell structure within fibrin enables controlled matrix remodeling to minimize wound contraction and fibrosis, and to promote GAG deposition. Level of Evidence Basic science study

Gamma secretase (GS) is an intramembraneous protease that cleaves over 91 different membrane substrates. GS is responsible for the final S3 cleavage of the notch receptor, thereby releasing the notch intracellular domain (NICD) into the cytoplasm. Upon translocation into the nucleus NICD activates the transcription of notch effector proteins that maintain cell stemness. Due to GS activity on the notch pathway, it has become an attractive target for cancer stem cells. The cancer stem cell (CSC) hypothesis states that cancers are generated and maintained by a group of cells that share similarities with normal adult stem cells. CSCs have been shown to be resistant to most current anti-cancer treatment approaches, including radiation therapy, thus contributing to tumor repopulation after therapy. A combinational therapy that targets both cancer cells and inhibits cancer stem cell growth is highly desirable. Unfortunately, there is inconsistent data determining the combinational effects of GS inhibitors (GSI) with radiation. In this study, the efficacy of GSI treatment with radiation therapy in reducing the cancer stem cell population in glioblastoma multiforme (GBM) was evaluated. Utilizing a panel of GBM cell lines varying in PTEN, p53, and EGFR status, we evaluated the effects of GSI plus radiation treatment on the cancer stem cell population, using sphere-forming capacity assays, cell cycle analysis, and γH2AX and Hoechst/PY staining. Our data demonstrates that PTEN status plays a role in the sensitivity to GSI treatment in combination with radiation treatment. In addition, we observed that treating PTEN-wt cell lines with GSI improved survival among the stem cell population while PTEN-mutant lines showed a reduced survival. We believe this glioma stem cell protection is mediated through FOXO, or the Forkhead class O transcription factors, which is positively regulated by functioning PTEN. In conclusion, this study demonstrates that the effectiveness of combinational treatment of GSI and radiation on glioma stem cells depends on the genetic background of the tumor. Specifically, PTENwt neurosphere cell lines are radioprotected under GSI treatment while PTEN-null neurosphere cell lines become more radiosensitivecycle analysis, and γH2AX and Hoechst/PY staining. Our data demonstrates that PTEN status plays a role in the sensitivity to GSI treatment in combination with radiation treatment. In addition, we observed that treating PTEN-wt cell lines with GSI improved survival among the stem cell population while PTEN-mutant lines showed a reduced survival. We believe this glioma stem cell protection is mediated through FOXO, or the Forkhead class O transcription factors, which is positively regulated by functioning PTEN. In conclusion, this study demonstrates that the effectiveness of combinational treatment of GSI and radiation on glioma stem cells depends on the genetic background of the tumor. Specifically, PTENwt neurosphere cell lines are radioprotected under GSI treatment while PTEN-null neurosphere cell lines become more radiosensitive.

Thyroid cancer presents significant diagnostic challenges due to its complex anatomy and diverse tissue types. This study leverages Dynamic Optical Contrast Imaging (DOCI), a label-free, real-time imaging technology, with machine learning to enhance tumor detection and segmentation. Using 23 DOCI filters, we applied Principal Component Analysis (PCA) for dimensionality reduction, k-nearest neighbors (k-NN) for classification, and U-Net models for segmentation. The approach achieved high accuracy in distinguishing tissue types, with PCA enabling clear clustering, k-NN classifying normal, follicular, and papillary tissues, and U-Net models achieving 96.34% and 92.02% accuracy for papillary and follicular segmentation, respectively. Filter importance analysis reduced input dimensionality without significantly compromising performance, highlighting the potential for optimized imaging protocols. These findings demonstrate DOCI's utility in improving diagnostic accuracy and tumor characterization in thyroid cancer and beyond, offering a foundation for personalized treatment planning and surgical precision.Competing Interest StatementThe authors have declared no competing interest.