Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into ß-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Comparison of health-related quality of life and cosmetic outcome between traditional gasless trans-axillary endoscopic thyroidectomy and modified gasless trans-axillary endoscopic thyroidectomy for patients with papillary thyroid microcarcinoma.

BACKGROUND: Gasless trans-axillary endoscopic thyroidectomy (GTET) has been proved to provide better cosmetic results; however, it has limitations as dissection of central neck lymph nodes is difficult. We developed a modified approach (MGTET-modified GTET) and compared it with the traditional one in terms of patients' health-related quality of life (HRQoL) and cosmetic results in order to provide more convincing therapeutic results. METHODS: Between January 2021 and June 2021, 100 cN0 patients who had a confirmed diagnosis of papillary thyroid microcarcinoma were randomized to undergo either MGTET (n = 50) or GTET (n = 50). These two groups' baseline characteristics, intraoperative and postoperative findings, were compared. The Patient and Observer Scar Assessment Scale (POSAS) was determined 6 months after surgery. Thyroid Cancer-Specific Quality of Life Questionnaire was used to assess HRQoL at 1, 3, 6, and 12 months after surgery. RESULTS: M-GTET was associated with a larger number of lymph nodes dissected (p < 0.001), lower drainage volume (p < 0.001), shorter hospital stay (p < 0.001), and shorter axillary incision (p < 0.001). POSAS was more favorable in M-GTET. HRQoL was significantly better for MGTET in terms of less problems with scar (p < 0.001). CONCLUSION: Our study suggests that MGTET provides better therapeutic, cosmetic, and HRQoL outcomes.

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation.

Ferrous iron (Fe2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe0 nanoparticles (Fe0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe0 -siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2 ). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0 -siRNA NPs. In addition to initiating chemodynamic process, Fe2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy.

As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)- and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both in vitro and in vivo results demonstrate that, compared with nitrogen-monodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.

Amplification of Lipid Peroxidation by Regulating Cell Membrane Unsaturation To Enhance Chemodynamic Therapy.

Lipid peroxidation (LPO) is one of the most damaging processes in chemodynamic therapy (CDT). Although it is well known that polyunsaturated fatty acids (PUFAs) are much more susceptible than saturated or monounsaturated ones to LPO, there is no study exploring the effect of cell membrane unsaturation degree on CDT. Here, we report a self-reinforcing CDT agent (denoted as OA@Fe-SAC@EM NPs), consisting of oleanolic acid (OA)-loaded iron single-atom catalyst (Fe-SAC)-embedded hollow carbon nanospheres encapsulated by an erythrocyte membrane (EM), which promotes LPO to improve chemodynamic efficacy via modulating the degree of membrane unsaturation. Upon uptake of OA@Fe-SAC@EM NPs by cancer cells, Fe-SAC-catalyzed conversion of endogenous hydrogen peroxide into hydroxyl radicals, in addition to initiating the chemodynamic therapeutic process, causes the dissociation of the EM shell and the ensuing release of OA that can enrich cellular membranes with PUFAs, enabling LPO amplification-enhanced CDT.

Singlet Oxygen Generation in Dark-Hypoxia by Catalytic Microenvironment-Tailored Nanoreactors for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Singlet oxygen (1 O2 ) has a potent anticancer effect, but photosensitized generation of 1 O2 is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of 1 O2 -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO42- catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO42- -catalyzed generation of 1 O2 from H2 O2 and protects MoO42- from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H2 O2 and 1 O2 can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent 1 O2 sensor to achieve monitored tumor CDT.

The Identification, Preservation and Classification of the External Branch of the Superior Laryngeal Nerve in Thyroidectomy.

BACKGROUND: Avoiding injury to the external branch of the superior laryngeal nerve is one of the major challenges during thyroid operation. The aim of this study was to propose a practical classification of the external branch of the superior laryngeal nerve. METHODS: A retrospective study of total thyroidectomy was performed. Totally 240 patients were included, with 480 external branches of the superior laryngeal nerves explored by intraoperative neuromonitoring. The classification of the external branch of the superior laryngeal nerve was determined by the distance between the upper edge of the superior thyroid pole and the lowest point of the nerve when the thyroid lobe was retracted in the lateral and inferior direction. Multinomial logistic regression analysis was run to predict the type of the nerve from several variables. RESULTS: The identification rate of the external branch of the superior laryngeal nerve was 98.54% (473 of 480 nerves). Higher ratio of longitudinal size of the thyroid lobe to ipsilateral neck length increased the likelihood of that both the type 2 and 3 nerve with respect to type 1 nerve, with OR 2.72, 95% CI = 1.21-6.12 and OR 5.30, 95% CI = 2.09-13.44, respectively. (1a) The nerve whose lowest point (entry into the muscle) was located more than 1 cm above the horizontal plane passing the upper border of superior thyroid pole. (1b) The nerve whose lowest point (the point right above the superior thyroid pole) was located more than 1 cm above the plane. (2a) The nerve whose lowest point (entry into the muscle) was located within 1 cm above the plane. (2b) The nerve whose lowest point (the point right above the superior thyroid pole) was located within 1 cm above the plane. (3a) The nerve whose lowest point (entry into the muscle) was located below the plane. (3b) The nerve whose lowest point (the point right below the superior thyroid pole) was located anterior to the gland. (3c) The nerve whose lowest point (the point right below the superior thyroid pole) was located posterior to the gland. CONCLUSIONS: Identification rate of the external branch of the superior laryngeal nerve by intraoperative neuromonitoring was significantly high. Understanding the new practical classification of the nerve allows for better identification and function preservation of this nerve during thyroidectomy.

RhoC is essential in TGF-ß1 induced epithelial-mesenchymal transition in cervical cancer cells.

Epithelial-mesenchymal transition (EMT) is a critical process in the promotion of epithelial tumor progression and metastasis. The present study aimed to investigate the role of Ras homolog gene family, member C (RhoC) guanosine triphosphatase (GTPase) in transforming growth factor (TGF)-ß1 induced EMT. EMT occurred in human cervical carcinoma SiHa cells following TGF-ß1 stimulation for 4 days, as demonstrated by the appearance of mesenchymal morphology, reorganization of the actin cytoskeleton, reduced E-cadherin expression and increased Vimentin expression, which was associated with increased RhoC expression and activity. However, EMT was not observed in cells that were pretreated with RhoC siRNA prior to TGF-ß1 stimulation. Downregulation of RhoC 4 days following TGF-ß1 stimulation was not able to reverse the existing EMT. In addition, TGF-ß1 promoted the invasion of the control SiHa cells but not that of the cells in which RhoC was downregulated. In conclusion, RhoC expression is activated by TGF-ß1, and sufficient RhoC expression levels are essential for TGF-ß1-induced EMT.

[Effects of levonorgestrel intrauterine system on endometrial tissue after endometrial polyps resection by hysteroscopy].

OBJECTIVE: To explore the changes of endometrial tissues after the insertion of levonorgestrel intrauterine system (LNG-IUS). METHODS: The endometrial tissues were harvested from 21 cases after endometrial polyps resection by hysteroscopy. And the patients received a 1-year follow-up. The immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), Ki-67, bcl-2 and bax were used for semi-quantitative analyses. The changes of endometrial thickness were monitored and uterine weight was observed with a 3-year follow-up. RESULTS: The endometrial thickness and uterine weight declined continuously after the insertion of LNG-IUS. The endometrial thickness decreased from the preoperative level of (9.8 ± 1.2) mm to (3.5 ± 1.0) mm while the uterine weight dropped from the preoperative level of (98.8 ± 8.6) g to (66.6 ± 9.8) g. The expressions of ER, PR and Ki-67 were significantly lower than those of the para-polyps endometrial tissue (P < 0.05). The expressions of bcl-2 and bax were significantly higher than those of the para-polyps endometrial tissue (P < 0.05). CONCLUSION: LNG-IUS may prevent the recurrence of uterine endometrial polyps through its inhibited expressions of ER, PR and Ki-67 and induced endometrial apoptosis.

The effect of RhoC siRNA on the invasiveness and proliferation of human cervical cancer cell line SiHa cells.

This study investigated the effect of RhoC GTPase on the proliferation and metastasis of cervical cancer cells, SiHa cells, in vitro. RhoC siRNA was introduced into SiHa cells to silence the RhoC gene. The mRNA and protein expression of RhoC, before and after RhoC siRNA transfection, was examined by RT-PCR and Western blotting, respectively. The proliferation and apoptosis of SiHa cells were examined by MTT assay and flow cytometry (FACS), respectively. Adhesive rate was evaluated by Matrigel adhesive assay, and the invasive capability and migration capability were assessed by transwell invasive assay and migration assay, respectively. The results showed that after the RhoC siRNA transfection, the mRNA and protein expression of RhoC was down-regulated in SiHa cells. The down-regulation of RhoC GTPase did not affect the cell proliferation and apoptosis (P>0.05), but it did suppress SiHa cells' adhesion to matrigel (P<0.01), the invasive capability (P<0.01) and the migration capability (P<0.01). It was concluded that RhoC obviously promotes the adhesion, invasion and migration of SiHa cells in vitro, but not proliferation and apoptosis, suggesting that RhoC plays an important role in the progression in cervical cancer.