Novel Withanolides from Tubocapsicum anomalum Suppress Triple-Negative Breast Cancer by Triggering Apoptosis and p53-ASCT2-SLC7A11-Mediated Ferroptosis.

Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe2+, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.

Decompression-first or direct enucleation: The choice of treatment for medium-sized odontogenic jaw cysts.

BACKGROUND: The treatment of medium-sized odontogenic jaw cysts is inconsistent at present. Two main treatments, namely decompression and enucleation, are used overlappingly. This retrospective analysis aims to provide useful references for technique selection for future management of medium-sized odontogenic jaw cysts. METHODS: Odontogenic cysts with lesion sizes ranging 2-4 cm were included. The clinical and radiological data of the patients were reviewed. Decompression-first and direct enucleation treatments were the two main surgical techniques. The preoperative parameters and postoperative outcomes were compared between the two groups. RESULTS: Out of 69 patients included, 40 (58 %) were in the decompression group and 29 (42 %) in direct enucleation group. The logistic regression analysis of preoperative parameters demonstrated that the maximum lesion size and the chief surgeon's preference could affect the selection of surgical techniques for medium-sized cysts (P < 0.05). Receiver operating characteristic curve analyses demonstrated that a lesion size >2.5 cm was the best cutoff value for predicting a decompression selection. Most postoperative outcomes differed significantly between the two groups (P < 0.05). Lower-risk anesthesia, shorter hospitalization, tooth function protection, and fewer neurosensory impairments were decompression-favoring outcomes. However, more follow-up visits, more postoperative X-rays, and longer postoperative care were outcomes against decompression. The recurrence rate was low and did not differ significantly between the two groups (P > 0.05). CONCLUSIONS: There is no apparent preference for treating medium-sized jaw cysts. The maximum lesion size is a moderate-impact factor for treatment selection. A tendency to prefer decompression-first with larger lesion size was found in medium-sized jaw cysts. The advantages of teeth preservation and low neurosensory impairment of decompression were verified in the medium-size jaw cysts. The burden of postoperative care should be considered when selecting decompression.

Robot-assisted augmented reality surgical navigation based on optical tracking for mandibular reconstruction surgery.

PURPOSE: This work proposes a robot-assisted augmented reality (AR) surgical navigation system for mandibular reconstruction. The system accurately superimposes the preoperative osteotomy plan of the mandible and fibula into a real scene. It assists the doctor in osteotomy quickly and safely under the guidance of the robotic arm. METHODS: The proposed system mainly consists of two modules: the AR guidance module of the mandible and fibula and the robot navigation module. In the AR guidance module, we propose an AR calibration method based on the spatial registration of the image tracking marker to superimpose the virtual models of the mandible and fibula into the real scene. In the robot navigation module, the posture of the robotic arm is first calibrated under the tracking of the optical tracking system. The robotic arm can then be positioned at the planned osteotomy after the registration of the computed tomography image and the patient position. The combined guidance of AR and robotic arm can enhance the safety and precision of the surgery. RESULTS: The effectiveness of the proposed system was quantitatively assessed on cadavers. In the AR guidance module, osteotomies of the mandible and fibula achieved mean errors of 1.61 ± 0.62 and 1.08 ± 0.28 mm, respectively. The mean reconstruction error of the mandible was 1.36 ± 0.22 mm. In the AR-robot guidance module, the mean osteotomy errors of the mandible and fibula were 1.47 ± 0.46 and 0.98 ± 0.24 mm, respectively. The mean reconstruction error of the mandible was 1.20 ± 0.36 mm. CONCLUSIONS: The cadaveric experiments of 12 fibulas and six mandibles demonstrate the proposed system's effectiveness and potential clinical value in reconstructing the mandibular defect with a free fibular flap.

Application of a modified osteotomy and positioning integrative template system (MOPITS) based on a truncatable reconstruction model in the precise mandibular reconstruction with fibula free flap: a pilot clinical study.

BACKGROUND: Mandibular defects can greatly affect patients' appearance and functionality. The preferred method to address this issue is reconstructive surgery using a fibular flap. The current personalized guide plate can improve the accuracy of osteotomy and reconstruction, but there are still some problems such as complex design process and time-consuming. Therefore, we modified the conventional template to serve the dual purpose of guiding the mandible and fibula osteotomy and facilitating the placement of the pre-bent titanium. METHODS: The surgery was simulated preoperatively using Computer-Aided Design (CAD) technology. The template and truncatable reconstruction model were produced in the laboratory using 3D printing. After pre-bending the titanium plate according to the contour, the reconstruction model was truncated and the screw trajectory was transferred to form a modified osteotomy and positioning integrative template system (MOPITS). Next, the patient underwent a composite template-guided vascularized fibula flap reconstruction of the mandible. All cases were reviewed for the total operative time and accuracy of surgery. RESULTS: The procedures involved 2-4 fibular segments in 15 patients, averaging 3 fibular segments per procedure. The osteotomy error is 1.01 ± 1.02 mm, while the reconstruction angular error is 1.85 ± 1.69°. The preoperative and postoperative data were compared, and both p > 0.05. During the same operation, implant placement was performed on four patients, with an average operative time of 487.25 ± 60.84 min. The remaining malignant tumor patients had an average operative time of 397.18 ± 73.09 min. The average postoperative hospital stay was 12.95 ± 3.29 days. CONCLUSIONS: This study demonstrates the effectiveness of MOPITS in facilitating precise preoperative planning and intraoperative execution of fibula flap reconstruction. MOPITS represents a promising and reliable tool for reconstructive surgery, particularly for inexperienced surgeons navigating the challenges of mandible defect reconstruction.

Rapid multi-task diagnosis of oral cancer leveraging fiber-optic Raman spectroscopy and deep learning algorithms.

Introduction: Oral cancer, a predominant malignancy in developing nations, represents a global health challenge with a five-year survival rate below 50%. Nonetheless, substantial reductions in both its incidence and mortality rates can be achieved through early detection and appropriate treatment. Crucial to these treatment plans and prognosis predictions is the identification of the pathological type of oral cancer. Methods: Toward this end, fiber-optic Raman spectroscopy emerges as an effective tool. This study combines Raman spectroscopy technology with deep learning algorithms to develop a portable intelligent prototype for oral case analysis. We propose, for the first time, a multi-task network (MTN) Raman spectroscopy classification model that utilizes a shared backbone network to simultaneously achieve different clinical staging and histological grading diagnoses. Results: The developed model demonstrated accuracy rates of 94.88%, 94.57%, and 94.34% for tumor staging, lymph node staging, and histological grading, respectively. Its sensitivity, specificity, and accuracy compare closely with the gold standard: routine histopathological examination. Discussion: Thus, this prototype proposed in this study has great potential for rapid, non-invasive, and label-free pathological diagnosis of oral cancer.

Giant calcifying epithelial odontogenic tumor after I-125 seed implantation: A case report.

Calcifying Epithelial Odontogenic Tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic benign tumor. It was first reported by Thoma and Goldman in 1946 and defined as an independent tumor by Pindborg in 1957. Herein, we reported a CEOT case involving most of the mandible after I-125 implantation in a 53-year-old man. We cooperated with governmental and hospital departments to resect the tumors, reconstruct the mandible with a fibular flap graft, and properly dispose of the radioactive particles.

Ganoderenic acid D-loaded functionalized graphene oxide-based carrier for active targeting therapy of cervical carcinoma.

Ganoderenic acid D (GAD), extracted from the Chinese herb Ganoderma lucidum, was loaded onto a graphene oxide-polyethylene glycol-anti-epidermal growth factor receptor (GO-PEG-EGFR) carrier to develop a targeting antitumor nanocomposite (GO-PEG@GAD). The carrier was fabricated from PEG and anti-EGFR aptamer modified GO. Targeting was mediated by the grafted anti-EGFR aptamer, which targets the membrane of HeLa cells. Physicochemical properties were characterized by transmission electron microscopy, dynamic light scattering, X-ray powder diffraction, and Fourier transform infrared spectroscopy. High loading content (77.3 % ± 1.08 %) and encapsulation efficiency (89.1 % ± 2.11 %) were achieved. Drug release continued for approximately 100 h. The targeting effect both in vitro and in vivo was confirmed by confocal laser scanning microscopy (CLSM) and imaging analysis system. The mass of the subcutaneous implanted tumor was significantly decreased by 27.27 ± 1.23 % after treatment with GO-PEG@GAD compared with the negative control group. Moreover, the in vivo anti-cervical carcinoma activity of this medicine was due to activation of the intrinsic mitochondrial pathway.

Innovative use of a self-expanding valve for valve-in-valve transcatheter mitral valve replacement: experience from a four-year single-center study.

Background: Valve-in-valve transcatheter mitral valve replacement (ViV-TMVR) is a minimally invasive option for patients with bioprosthetic mitral valve failure. Since January 2019, our center has been using a new innovative option, J-Valve, to treat patients with bioprosthetic mitral valve failure who were at high risk for open heart surgery. The aim of this study is to explore the effectiveness and safety of J-Valve and report the results from the four-year follow-up period of the innovative application of the transcatheter valve. Methods: Patients who underwent the ViV-TMVR procedure between January 2019 and September 2022 in our center were included in the study. J-Valve™ system (JC Medical Inc., Suzhou, China) with three U-shape grippers was used for ViV-TMVR via transapical approach. Data on survival, complications, transthoracic echocardiographic results, New York Heart Association functional class in heart failure, and patient-reported health-related quality of life according to the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) were collected during the four-year follow up. Results: Thirty-three patients (mean age 70.1 ± 1.1 years, 13 men) were included and received ViV-TMVR. The surgery success rate was 97%: only one patient was converted to open-heart surgery due to intraoperative valve embolization to the left ventricle. During the first 30 days all-cause mortality was 0%, risk of stroke 2.5% and risk of mild paravalvular leak 15.2%; mitral valve hemodynamics improved (179.7 ± 8.9 at 30 days vs. 269 ± 49 cm/s at baseline, p < 0.0001). Median time from operation to discharge was six days, and there were no readmissions within 30 days from operation. The median and maximum follow-up durations were 28 and 47 months, respectively; during the entire follow-up, all-cause mortality was 6.1%, and the risk of cerebral infarction 6.1%. Cox regression analysis did not identify any variables significantly associated with survival. The New York Heart Association functional class and the KCCQ-12 score improved significantly compared with their preoperative values. Conclusion: The use of J-Valve for ViV-TMVR is safe and effective with a high success rate, low mortality and very few associated complications, representing an alternative surgical strategy for the elderly, high-risk patients with bioprosthetic mitral valve failure.

Prediction of Male Coronary Artery Bypass Grafting Outcomes Using Body Surface Area Weighted Left Ventricular End-diastolic Diameter: Multicenter Retrospective Cohort Study.

BACKGROUND: The presence of a high left ventricular end-diastolic diameter (LVEDD) has been linked to a less favorable outcome in patients undergoing coronary artery bypass grafting (CABG) procedures. However, by taking into consideration the reference of left ventricular size and volume measurements relative to the patient's body surface area (BSA), it has been suggested that the accuracy of the predicting outcomes may be improved. OBJECTIVE: We propose that BSA weighted LVEDD (bLVEDD) is a more accurate predictor of outcomes in patients undergoing CABG compared to simply using LVEDD alone. METHODS: This study was a comprehensive retrospective cohort study that was conducted across multiple medical centers. The inclusion criteria for this study were patients who were admitted for treatment between October 2016 and May 2021. Only elective surgery patients were included in the study, while those undergoing emergency surgery were not considered. All participants in the study received standard care, and their clinical data were collected through the institutional registry in accordance with the guidelines set forth by the Society of Thoracic Surgeons National Adult Cardiac Database. bLVEDD was defined as LVEDD divided by BSA. The primary outcome was in-hospital all-cause mortality (30 days), and the secondary outcomes were postoperative severe adverse events, including use of extracorporeal membrane oxygenation, multiorgan failure, use of intra-aortic balloon pump, postoperative stroke, and postoperative myocardial infarction. RESULTS: In total, 9474 patients from 5 centers under the Chinese Cardiac Surgery Registry were eligible for analysis. We found that a high LVEDD was a negative factor for male patients' mortality (odds ratio 1.44, P<.001) and secondary outcomes. For female patients, LVEDD was associated with secondary outcomes but did not reach statistical differences for morality. bLVEDD showed a strong association with postsurgery mortality (odds ratio 2.70, P<.001), and secondary outcomes changed in parallel with bLVEDD in male patients. However, bLVEDD did not reach statistical differences when fitting either mortality or severer outcomes in female patients. In male patients, the categorical bLVEDD showed high power to predict mortality (area under the curve [AUC] 0.71, P<.001) while BSA (AUC 0.62) and LVEDD (AUC 0.64) both contributed to the risk of mortality but were not as significant as bLVEDD (P<.001). CONCLUSIONS: bLVEDD is an important predictor for male mortality in CABG, removing the bias of BSA and showing a strong capability to accurately predict mortality outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02400125; https://clinicaltrials.gov/ct2/show/NCT02400125.

Shikonin and cisplatin synergistically overcome cisplatin resistance of ovarian cancer by inducing ferroptosis via upregulation of HMOX1 to promote Fe2+ accumulation.

BACKGROUND: Cisplatin-based chemotherapy often results in ovarian cancer (OC) chemical resistance and treatment failure. The combination of natural compounds with platinum-based agents is a new strategy for overcoming cisplatin resistance. At present, the synergistic effects and mechanism of combination of shikonin and cisplatin to overcome cisplatin resistance in OC are still unknown. PURPOSE: This study was to evaluate the synergistic effects of shikonin and cisplatin on cisplatin-resistant OC cells and to assess the underlying molecular basis for these effects. METHODS: Cell counting kit-8 assay, colony-formation assay, proteomic analysis, reactive oxygen species (ROS) detection, lipid peroxidation (LPO) detection, Fe2+ detection, western blot, and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to evaluate the effects of shikonin and cisplatin on cisplatin-resistant OC cells. Underlying mechanisms of action were investigated in vitro using small molecule inhibitors and siRNA. In vivo, the effect of shikonin and cisplatin combination on tumor growth in BALB/c nude mice was evaluated, with tumor immunohistochemical (IHC) staining performed to detect ferroptosis-related proteins. RESULTS: In vitro, shikonin and cisplatin were shown to synergistically reduce the viability of cisplatin-resistant OC cells. Proteomic results demonstrated that the combination of the two drugs induced a ferroptotic process, as evidenced by increased levels of ROS, LPO, and Fe2+, with downregulation of glutathione peroxidase 4 (GPX4). Heme oxygenase 1 (HMOX1) inhibition and siRNA interference attenuated the combined effect of the two drugs on cell viability. Accumulation of Fe2+ was attenuated by siRNA interference of HMOX1. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and increased the expression of ferroptosis-related proteins in tumor tissue. CONCLUSION: We report for the first time that the co-treatment of shikonin and cisplatin overcomes cisplatin resistance in OC through ferroptosis. Mechanistic analysis reveals the co-treatment induces ferroptosis through upregulation of HMOX1 that promotes Fe2+ accumulation.

A novel sesquiterpene lactone fraction from Eupatorium chinense L. suppresses hepatocellular carcinoma growth by triggering ferritinophagy and mitochondrial damage.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive tumor with limited treatment options, and it is the third leading cause of cancer-related deaths. Hence, novel therapeutic strategies are required to treat HCC. Eupatorium chinense L. is a traditional Chinese medicine (TCM) that can effectively neutralize heat and smoothen the flow of "Qi" through the liver. However, the anti-HCC effects of Eupatorium chinense L. remain unknown. PURPOSE: The present study investigated the anti-HCC effects and the underlying mechanisms of the electrophilic sesquiterpenes isolated from E. chinense L. (EChLESs) in the regulation of ferroptosis and apoptosis in HCC cells. STUDY DESIGN/METHODS: Cell viability was assessed by the MTT assay. Cell apoptosis was confirmed by flow cytometry and western blotting assay. Ferroptosis was assessed by flow cytometry, transmission electron microscopy, and western blotting assay. Ferritinophagy was detected by acridine orange staining and western blotting assay. Small interfering RNA of nuclear receptor coactivator 4 (NCOA4) was used to confirm the role of ferritinophagy in the therapeutic effect of EChLESs on HCC cells. A mouse xenograft model was constructed to determine the inhibitory effect of EChLESs on HCC in vivo. RESULTS: EChLESs induced apoptosis by disrupting mitochondrial membrane potential depolarization and mitochondrial reactive oxygen species. EChLESs induced ferroptosis as noted by a significant increase in mitochondrial disruption, lipid peroxidation, and intracellular iron level and decreased glutathione level. The apoptosis inhibitor Z-VAD-FMK and lipid reactive oxygen species scavenger ferrostatin 1 attenuated EChLESs-induced cell death. NCOA4-mediated ferritinophagy through autophagic flux was the crucial pathway for ferroptosis induced by EChLESs. NCOA4 knockdown alleviated EChLESs-induced cell death. EChLESs controlled the expression of NCOA4 at the transcriptional and post-transcriptional levels. In the in vivo experiment, EChLESs suppressed HCC growth in the xenograft tumor mouse model. CONCLUSION: EChLESs enhances cell apoptosis through mitochondrial dysfunction and ferroptosis through NCOA4-mediated ferritinophagy. Thus, Eupatorium chinense L. could be a potential TCM for treating HCC.

Detachable Dual-Targeting Nanoparticles for Improving the Antitumor Effect by Extracellular Matrix Depletion.

In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor ß by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.

Cardioprotective effect of crude polysaccharide fermented by Trametes Sanguinea Lyoyd on doxorubicin-induced myocardial injury mice.

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its clinical application is greatly limited because of the cardiotoxicity. Thus, exploration of effective therapies against DOX-induced cardiotoxicity is necessary. The aim of this study is to investigate the effects and possible mechanisms of Trametes Sanguinea Lyoyd fermented crude polysaccharide (TSLFACP) against DOX-induced cardiotoxicity. We investigated the protective effects of TSLFACP on myocardial injury and its possible mechanisms using two in vitro cells of DOX-treated cardiomyocytes H9C2 and embryonic myocardial cell line CCC-HEH-2 and a in vivo mouse model of DOX-induced myocardial injury. We found that TSLFACP could reverse DOX-induced toxicity in H9C2 and CCC-HEH-2 cells. Similarly, we found that when pretreatment with TSLFACP (200 mg/kg, i.g.) daily for 6 days, DOX-induced myocardial damage was attenuated, including the decrease in serum myocardial injury index, and the amelioration in cardiac histopathological morphology. Additionally, immunohistochemistry and western blotting were used to identify the underlying and possible signal pathways. We found that TSLFACP attenuated the expression of LC3-II, Beclin-1 and PRAP induced by DOX. In conclusion, our results demonstrated that TSLFACP could protect against DOX-induced cardiotoxicity by inhibiting autophagy and apoptosis.

Augmented reality guided in reconstruction of mandibular defect with fibular flap: A cadaver study.

BACKGROUND: Augmented reality (AR) navigation has been developed in recent years and can overcome some limitations of existing technologies. This study aimed to investigate a novel method of fibula free flap (FFF) osteotomy based on AR technology through a cadaver study. METHODS: One mandible, seven fibulas, and seven lower limb specimens underwent computed tomography (CT) examination. We used the professional software Proplan CMF 3.0 to design a defective mandible model and created fourteen virtual reconstruction plans using the fibulas and lower limb specimens. The AR-based intraoperative guidance software prototype was developed using the Unity Real-Time Development Platform, and virtual plans were transferred into this software prototype. We used AR-based surgical navigation to guide the FFF osteotomy and used these fibular segments to reconstruct the defective mandible model. After reconstruction, all segments were scanned by CT. Osteotomy accuracy was evaluated by measuring the length and angular deviation between the virtual plan and the final result. The reconstruction precision was reflected by the volume overlap rate and average surface distance between the planned and obtained reconstruction. RESULTS: The length difference, angular deviation, volume overlap rate and average surface distance of the in vitro group were 1.03±0.68 mm, 5.04±2.61°, 95.35±1.81%, and 1.02±0.27 mm, respectively. Those of the in vivo group were 1.18±0.84 mm, 5.45±1.47°, 95.31±2.09%, and 1.22±0.12 mm. CONCLUSIONS: Due to the ideal result of cadaver experiments, an AR-based FFF osteotomy guided system may become a novel approach to assist FFF osteotomy for the reconstruction of defective mandibles.

Multiple Strikes Achieve Remarkable Tumor-Inhibition Efficiency via Multi-mechanism Combination.

Breast cancer treatment has been challenging all the time because cancer cells have multiple signaling pathways; so, breast cancer still remains a threat to the lives and health of many patients. While common single drug therapies inhibit only one pathway, the combination of multiple mechanisms offers the potential to simultaneously suppress multiple targets and pathways to kill cancer cells more effectively. It is reported that autophagy caused by autophagy inducers and apoptosis caused by some chemotherapeutic drugs can promote ferroptosis to some extent; herein, we combined these three pathways and constructed a multifunctional dual-responsive release nanosystem of Rap@mFe3O4-DOX-HA that achieved the ferroptosis-autophagy-apoptosis synergistic effect for cancer treatment. Mesoporous Fe3O4 (mFe3O4) was set as the carrier and can also release Fe ions for ferroptosis, the autophagy inducer rapamycin (Rap) was wrapped in the carrier to trigger autophagy, and the chemotherapeutic drug doxorubicin (DOX) was used as the apoptosis inducer. At the tumor site, the prepared Rap@mFe3O4-DOX-HA nanoparticles split and released DOX/Rap in response to H+/GSH. From in vivo and in vitro studies, it was found that Rap@mFe3O4-DOX-HA nanoparticles effectively inhibited the migration of 4T1 cells, furthermore, they struck cancer cells through multiple pathways and greatly improved the anti-tumor effect. Therefore, the strategy of multi-mechanism combination achieved a therapeutic effect of 1 + 1 > 2.

Prognostic role of PD-L1 expression in patients with salivary gland carcinoma: A systematic review and meta-analysis.

BACKGROUND: Although programmed cell death-ligand 1 (PD-L1) has been recognized as a potential marker in several cancers, the relationship between PD-L1 expression and survival in patients with salivary gland carcinoma (SGC) has remained unclear. We aimed to evaluate the association of PD-L1 expression with clinicopathological features and prognosis in SGC patients. METHODS: The databases Ovid Medline, PubMed, Scopus, and EMBASE were searched for relevant studies that detected PD-L1 expression in SGC. The meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA), and the reporting recommendations for tumor marker prognostic studies (REMARK) was used to assess the quality of research eligible for this meta-analysis. Included studies were assessed using the Quality in Prognosis Studies (QUIPS) tool. Odds ratios (ORs) with 95% confidence interval (CI) were calculated to estimate the correlation between PD-L1 expression and clinicopathological features. Hazard ratios (HRs) with 95% CI were applied to assess the association between PD-L1 expression and survival outcomes of patients. RESULTS: A total of ten studies (including 952 patients with SGC) were evaluated. The meta-analysis showed that positive PD-L1 expression in SGC was significantly associated with male patients, older age, Tumor stage, lymph node metastasis, high pathological grade, and non-adenoid cystic carcinoma subtype. The pooled data demonstrated that high PD-L1 expression was associated with poor overall survival and disease-free survival. There was no significant correlation between PD-L1 expression and progression-free survival or disease-specific survival of SGC patients. CONCLUSION: According to the meta-analysis, positive PD-L1 expression may play an important role as an effective marker of poor prognosis in patients with SGC. However, large-scale, prospective investigations are still needed to confirm the findings. The assessment of PD-L1 expression may aid in the personalized management of SGC.

Cascade nanozymes based on the "butterfly effect" for enhanced starvation therapy through the regulation of autophagy.

Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency may be weakened by autophagy, a self-protection mechanism exerted by tumors under starvation stress. Interestingly, over-activated autophagy not only improves the efficacy of starvation therapy, but also induces autophagic death. Herein, we report cascade nanozymes for enhanced starvation therapy by inducing over-activated autophagy. First, glucose oxidase (GOx) modified metal-organic frameworks (NH2-MIL88, MOF) were constructed (MOF-GOx). After loading with curcumin (Cur), Cur@MOF-GOx was further decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozymes. GOx can catalyze glucose into H2O2 and gluconic acid, which not only leads to tumor starvation, but also provides reactants for the Fenton reaction mediated by the MOF to generate hydroxyl radicals (˙OH) for chemo-dynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be over-activated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemo-dynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a "butterfly effect", which induces enhanced starvation therapy through subsequent autophagic cell death to completely break the self-protective mechanism of cancer cells, and generate ˙OH for chemo-dynamic therapy. Precise design allows for the use of cascade nanozymes to realize efficient cancer treatment and restrain metastasis.

Eupaformosanin induces apoptosis and ferroptosis through ubiquitination of mutant p53 in triple-negative breast cancer.

The mutant p53 plays a vital role in the control of cell survival and division under various stresses, including apoptosis and ferroptosis. Here, we showed that eupaformosanin (Eup), a natural compound isolated from Eupatorium cannabinum Linn., significantly inhibited the viability of triple-negative breast cancer (TNBC) cells. Meanwhile, mitochondrial apoptosis contributed to the apoptosis induced by Eup, followed by the disruption of mitochondrial membrane potential (MMP; Δψm) and accumulation of mitochondrial ROS (mt ROS). Apoptosis inhibitor Z-VAD rescued Eup-induced cell death. Afterward, ferroptosis-induced cell death was demonstrated after treatment with Eup, accompanied by lipid reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and iron increase. These events were blocked by ferroptosis inhibitors ferrostatin-1 (Fer-1), deferoxamine (DFO), and liproxstatin-1 (lip-1), indicating that ferroptosis facilitated Eup-induced cell death. Furthermore, Eup regulated mutant p53 ubiquitination. Mutant p53 signaling pathway participated in Eup-induced apoptosis and ferroptosis, which were rescued when mutant p53 was silent in TNBC cells. Also, Eup exerted an anti-TNBC effect by inducing apoptosis and ferroptosis in vivo. Taken together, the data demonstrate that the natural compound Eup is a potential TNBC therapeutic agent that induces apoptosis and ferroptosis through ubiquitination of mutant p53.

[The Effects of Different Adaptive Statistical Iterative Reconstruction-V and Convolution Kernel Parameters on Auto-Segmentation Stability in CT Images].

Objective The study aims to investigate the effects of different adaptive statistical iterative reconstruction-V（ ASiR-V） and convolution kernel parameters on stability of CT auto-segmentation which is based on deep learning. Method Twenty patients who have received pelvic radiotherapy were selected and different reconstruction parameters were used to establish CT images dataset. Then structures including three soft tissue organs (bladder, bowelbag, small intestine) and five bone organs (left and right femoral head, left and right femur, pelvic) were segmented automatically by deep learning neural network. Performance was evaluated by dice similarity coefficient（ DSC） and Hausdorff distance, using filter back projection(FBP) as the reference. Results Auto-segmentation of deep learning is greatly affected by ASIR-V, but less affected by convolution kernel, especially in soft tissues. Conclusion The stability of auto-segmentation is affected by parameter selection of reconstruction algorithm. In practical application, it is necessary to find a balance between image quality and segmentation quality, or improve segmentation network to enhance the stability of auto-segmentation.

Neutral Sphingomyelinase 2 Mediates Oxidative Stress Effects on Astrocyte Senescence and Synaptic Plasticity Transcripts.

We have shown that deficiency of neutral sphingomyelinase 2 (nSMase2), an enzyme generating the sphingolipid ceramide, improves memory in adult mice. Here, we performed sphingolipid and RNA-seq analyses on the cortex from 10-month-old nSMase2-deficient (fro/fro) and heterozygous (+ /fro) mice. fro/fro cortex showed reduced levels of ceramide, particularly in astrocytes. Differentially abundant transcripts included several functionally related groups, with decreases in mitochondrial oxidative phosphorylation and astrocyte activation transcripts, while axon guidance and synaptic transmission and plasticity transcripts were increased, indicating a role of nSMase2 in oxidative stress, astrocyte activation, and cognition. Experimentally induced oxidative stress decreased the level of glutathione (GSH), an endogenous inhibitor of nSMase2, and increased immunolabeling for ceramide in primary + /fro astrocytes, but not in fro/fro astrocytes. ß-galactosidase activity was lower in 5-week-old fro/fro astrocytes, indicating delayed senescence due to nSMase2 deficiency. In fro/fro cortex, levels of the senescence markers C3b and p27 and the proinflammatory cytokines interleukin 1ß, interleukin 6, and tumor necrosis factor α were reduced, concurrent with twofold decreased phosphorylation of their downstream target, protein kinase Stat3. RNA and protein levels of the ionotropic glutamate receptor subunit 2B (Grin2b/NR2B) were increased by twofold, which was previously shown to enhance cognition. This was consistent with threefold reduced levels of exosomes carrying miR-223-3p, a micro-RNA downregulating NR2B. In summary, our data show that nSMase2 deficiency prevents oxidative stress-induced elevation of ceramide and secretion of exosomes by astrocytes that suppress neuronal function, indicating a role of nSMase2 in the regulation of neuroinflammation and cognition.