Flourishing tumor organoids: History, emerging technology, and application.

Malignant tumors are one of the leading causes of death which impose an increasingly heavy burden on all countries. Therefore, the establishment of research models that closely resemble original tumor characteristics is crucial to further understanding the mechanisms of malignant tumor development, developing safer and more effective drugs, and formulating personalized treatment plans. Recently, organoids have been widely used in tumor research owing to their advantages including preserving the structure, heterogeneity, and cellular functions of the original tumor, together with the ease of manipulation. This review describes the history and characteristics of tumor organoids and the synergistic combination of three-dimensional (3D) culture approaches for tumor organoids with emerging technologies, including tissue-engineered cell scaffolds, microfluidic devices, 3D bioprinting, rotating wall vessels, and clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9). Additionally, the progress in research and the applications in basic and clinical research of tumor organoid models are summarized. This includes studies of the mechanism of tumor development, drug development and screening, precision medicine, immunotherapy, and simulation of the tumor microenvironment. Finally, the existing shortcomings of tumor organoids and possible future directions are discussed.

Association of matrix metalloproteinase-9 and nitric oxide with hypertension in obstructive sleep apnea.

Background: Patients with obstructive sleep apnea (OSA) are more likely to suffer from hypertension. At the same time, the serum levels of matrix metalloproteinase-9 (MMP-9) and nitric oxide (NO) in patients with OSA are also changed in OSA patients. We investigated the correlation between serum levels of MMP-9, NO in patients with OSA and their association with hypertension in those patients, and the effects of continuous positive airway pressure therapy (CPAP) on these serum biomarkers and blood pressure. Methods: Serum MMP-9 and NO levels and blood pressure of 57 patients with newly diagnosed OSA and 30 controls were measured; among them, 30 patients with moderate to severe OSA underwent 3-month CPAP treatment. Results: In comparison to the control group, the MMP-9 serum levels were higher (232.8 ± 103.2 ng/ml versus 161.6 ± 56.5 ng/ml, p < .001*), there was no statistical significance difference among serum NO (26.7 ± 9.1 IU/ml versus 31.0 ± 11.7 IU/ml, p = .06), and MMP-9 was negatively correlated to NO, especially in patients with hypertension (r = -.644, p = .02*). MMP-9, NO, and blood pressure were significantly recovered in the patients with OSA after CPAP treatment for 3 months (p < .05*). Conclusion: The MMP-9 level and the NO level were altered in OSA patients. The relationship between the two especially in patients with hypertension suggests the potential mechanism of OSA-induced hypertension.

Salvaged, Staged, and Safer Management of Aortoesophageal Fistula and Mediastinitis After Removing a Pork Bone: A Case Report.

Aortoesophageal fistula (AEF) caused by esophageal foreign body (EFB) ingestion is a life-threatening condition with a very low survival rate. However, the optimal management strategy remains undetermined. Here, we describe our successful management of a patient with AEF and mediastinitis. A 36-year-old man developed persistent chest and back pain and vomited fresh blood three days after removal of a pork bone in the esophagus under endoscopy in a local hospital. Computed tomography (CT) confirmed bilateral pulmonary infections, mediastinitis, and fistula of the aortic arch. After a multidiscipline discussion, a comprehensive staged strategy was made including salvaged thoracic endovascular aortic repair (TEVAR) to control fatal bleeding, adequate mediastinal debridement, drainage with cervical incision, and video-assisted thoracoscopic surgery, as well as jejunostomy to prevent nasal or gastrostomy reflux from aggravating the mediastinal infection. Furthermore, systematic personalized nutrition support and antibiotics were provided. The patient recovered well and has survived for 50 months until now. Careful assessment should be made with CT to ascertain the risk of AEF before and after the removal of EFB. A salvaged staged strategy of TEVAR with adequate mediastinal debridement and drainage in a less invasive approach may be a safer alternative for AEF patients with infections caused by EFB.

Zone-specific damage of the olfactory epithelium under protein restriction.

Oxidative stress causes tissue damage, affecting age-related pathologies. Protein restriction (PR) provides a powerful intervention strategy for reducing oxidative stress, which may have a positive effect on individual organs. However, it is unknown whether PR intervention influences the olfactory system. Here, we investigated how 10 months of PR could affect the cell dynamics of the olfactory epithelium (OE) in mice. We found that PR reduced age-related loss of outer hair cells in the cochlea, providing preventive effects against age-related hearing loss. In contrast, PR resulted in reduced mature olfactory sensory neurons (OSNs), increased proliferative basal cells, and increased apoptotic OSNs in zone 1 (the only area containing neurons expressing NQO1 [quinone dehydrogenase 1]) of the OE in comparison with animals given a control diet. Substantial oxidative stress occurred in NQO1-positive cells and induced apoptotic OSNs in zone 1. These results indicate that in contrast to the positive effect on the auditory system, PR induces oxidative stress and structurally and functionally negative effects on OSNs in zone 1, which is probably involved in the bioactivation of NQO1.

Clinical significance of neuropilin-2 expression in laryngeal squamous cell carcinoma.

PURPOSE: The purpose of the study is to evaluate the expression of NRP-2 and explore its role in Laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: NRP-2 expression in 70 primary LSCC tissue specimens were analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients´ survival rate. Additionally, 9 paired LSCC tissues were evaluated for NRP-2 expression by Western blotting. RESULTS: The Western blotting indicated that NRP-2 expression levels in LSCC were significantly higher than those in the paraneoplastic tissues (P < 0.05). Immunohistochemistry staining revealed that NRP-2 was detected in all primary tumor samples, moreover, high expression of NRP-2 was significantly correlated with TNM stage (P < 0.05), clinical stage (P < 0.05), histological classification (P < 0.05), lymph node metastasis (P < 0.05) and recurrence (P = 0.001). Survival curves determined by the Kaplan-Meier method showed that high expression of NRP-2 can reduce overall survival (both group P < 0.05). Then we combined the NRP-2 expression and lymph node status, and Kaplan-Meier survival showed patients with high expression of NRP-2 or lymph node metastasis (+) had both shorter disease-free and overall survival than others (both P < 0.05). Multivariate Cox proportional hazards model analysis confirmed that histological grade (P = 0.045), lymph node metastasis (P = 0.020) and high expression of NRP-2 (P = 0.033) were statistically significant, independent predictor of prognosis. CONCLUSIONS: NRP-2 may contribute to LSCC progression and represents as a novel prognostic indicator as well as a potential therapeutic target for LSCC.

Dorsal-zone-specific reduction of sensory neuron density in the olfactory epithelium following long-term exercise or caloric restriction.

Exercise (Ex) and caloric restriction (CR) reduce oxidative stress and improve organ function. For instance, voluntary Ex or CR is known to reduce age-related cochlear damage in male C57BL/6J mice. However, the effect of Ex and CR on the olfactory system is unknown. In this study, we confirmed the positive effect of Ex and CR on age-related cochlear damage, but found that Ex and CR affected negatively cell dynamics in the olfactory epithelium (OE) by reducing the number of mature olfactory sensory neurons (OSNs) and increasing the number of proliferative basal cells and apoptotic OSNs in the dorsal zone of the olfactory epithelium (OE), which contains neurons expressing NADPH quinone oxido-reductase 1 (NQO1). In addition, these interventions resulted in lower odor-induced c-fos expression in areas of the olfactory bulb receiving projections from dorsal-zone OSNs than in areas receiving ventral-zone projections. Further, we observed substantial oxidative stress in NQO1-positive cells and apoptotic OSNs in the dorsal zone in Ex and CR animals. These results suggest that, in contrast to their positive effects in other organs, Ex and CR facilitate oxidative stress and negatively impact structure and function in dorsal-zone OSNs, probably in association with NQO1 bioactivation.

Manganese superoxide dismutase influences the extent of noise-induced hearing loss in mice.

Reactive oxygen species (ROS) generation is one of the mechanisms underlying noise-induced hearing loss (NIHL). Manganese superoxide dismutase (Mn-SOD), an antioxidant enzyme acting within the mitochondria, converts toxic superoxide to hydrogen peroxide. We investigated the role of Mn-SOD in NIHL by examining the extent of hearing loss and hair cell damage after noise exposure in C57BL/6 wild-type (WT) mice and Mn-SOD heterozygous knockout (HET) mice (n=6 each). Both HET and WT mice were exposed to 120dB sound pressure level at 4kHz octave band noise for 4h. Auditory brainstem responses (ABRs) were used to evaluate hearing thresholds before noise exposure, and at 1h, and 1, 3, 7, and 14days after exposure. The mice were euthanized 14days after noise exposure for examination of the cochlear pathology. Mean ABR thresholds were similarly elevated at all frequencies in both groups 1h after noise exposure, but were significantly worse, particularly at 4kHz, on post-noise exposure days 7 and 14 in HET mice compared with WT mice. Outer hair cell damage was significantly greater in all cochlear turns in HET mice compared with WT mice. Collectively, these findings suggest that Mn-SOD plays an important role in protecting the cochlea from noise-induced damage.