Comparison of the effect of moxibustion at "Zusanli" (ST36) on the polarization of synovial macrophages of knee joints in rats with knee osteoarthritis and rheumatoid arthritis. / 艾灸"足三里"å¯¹è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žä¸Žç±»é£Žæ¹¿æ€§å ³èŠ‚ç‚Žå¤§é¼ è†å ³èŠ‚æ»‘è†œå·¨å™¬ç»†èƒžæžåŒ–çš„å½±å“çš„æ¯”è¾ƒç ”ç©¶.

OBJECTIVES: To observe the similarities and differences of effects of moxibustion at "Zusanli" (ST36) on target tissues and macrophages polarization in knee osteoarthritis (KOA) and rheumatoid arthritis (RA) rats, and to summarize its efficacy and characteristics. METHODS: Thirty rats were equally and randomly divided into control, KOA, RA, KOA+Moxi and RA+Moxi groups. The KOA model and RA model were induced by injection of sodium monoiodoacetate or Freund's complete adjuvant into the rats' knee joints, respectively. Rats of the KOA+Moxi and RA+Moxi groups received moxibustion stimulation at bilateral ST36 for 30 min, once a day for 21 days, beginning from the 7th day on after modeling. The contents of serum interleukin(IL)-1ß and IL-10 were detected by ELISA. Histopathological changes (Markin score of the knee cartilage and synovial pathology score) of the knee joints were observed after HE staining. The polarization state of M1 and M2 macrophages in the synovial tissue of the knee joints was assessed by detecting the expression of CD86 and CD206 after immunofluorescence staining. RESULTS: Compared with the control group, the content of serum IL-1ß, synovial pathology score, and synovial CD86 expression were significantly increased (P<0.01, P<0.05), while the content of serum IL-10 and synovial CD206 expression markedly decreased (P<0.01) in both KOA and RA groups；the Markin score was increased (P<0.01) in the KOA group. In comparison with the KOA group, the Markin score was obviously decreased (P<0.01), while the content of serum IL-10 and CD206 expression were apparently increased (P<0.01) in the KOA+Moxi group. No significant changes were found in the content of serum IL-1ß, synovial pathology score and CD86 expression in the KOA+Moxi group relevant to the KOA group. In comparison with the RA group, the content of serum IL-1ß, synovial pathology score, and CD86 expression were considerably decreased (P<0.01) in the RA+Moxi group. No marked differences were found in the serum IL-10 level, Markin score, and CD206 expression between RA+Moxi and RA model groups. The increased Markin score was significantly higher in the KOA group than in the RA group (P<0.01), but the increased synovial pathology score was significantly lower in the KOA group than in the RA group (P<0.01). Correspondingly, the effect of moxibustion at ST36 was significantly better in RA model than in KOA model in reducing serum IL-1ß (P<0.05). CONCLUSIONS: Moxibustion at ST36 can effectively reduce cartilage injury of knee joint in rats with KOA and reduce synovial injury in rats with RA, which may be related with its effects in lowering IL-1ß level in RA model by inhibiting the polarization of M1 macrophages, and up-regulating level of IL-10 in KOA model by promoting the polarization of M2 macrophages. However, the relevant mechanism needs to be further studied.

Permanent Shape Reconfiguration and Locally Reversible Actuation of a Carbon Nanotube/Ethylene Vinyl Acetate Copolymer Composite by Constructing a Dynamic Cross-Linked Network.

Given the rapid developments in modern devices, there is an urgent need for shape-memory polymer composites (SMPCs) in soft robots and other fields. However, it remains a challenge to endow SMPCs with both a reconfigurable permanent shape and a locally reversible shape transformation. Herein, a dynamic cross-linked network was facilely constructed in carbon nanotube/ethylene vinyl acetate copolymer (CNT/EVA) composites by designing the molecular structure of EVA. The CNT/EVA composite with 0.05 wt % CNT realized a steady-state temperature of ∼75 °C under 0.11 W/cm2 light intensity, which gave rise to remote actuation behavior. The dynamic cross-linked network along with a wide melting temperature offered opportunities for chemical and physical programming, thus realizing the achievement of the programmable three-dimensional (3D) structure and locally reversible actuation. Specifically, the CNT/EVA composite exhibited a superior permanent shape reconfiguration by activating the dynamic cross-linked network at 140 °C. The composite also showed a high reversible deformation rate of 11.1%. These features endowed the composites with the capability of transformation to 3D structure as well as locally reversible actuation performance. This work provides an attractive guideline for the future design of SMPCs with sophisticated structures and actuation capability.

Polyvinylpyrrolidone induced uniform coating of nickel nanoparticles on carbon nanotubes for efficient microwave absorption.

The impedance matching performance of carbon nanotubes (CNTs) can be effectively enhanced by developing a uniform magnetic impedance matching layer, which can take on critical significance in achieving the desirable microwave absorption (MA) performance. To obtain a uniform coating of Nickel (Ni) nanoparticles on CNTs, several methods have been developed (e.g., the γ-irradiation technique, electroless deposition, as well as microwave welding method). However, the intricate and complicated conditions of the above-mentioned methods limit their wide application. Therefore, controlling the distribution of Ni nanoparticles with the aid of a concise and effective method remains a great challenge. Herein, in view of the uniform dispersion effect of polyvinylpyrrolidone (PVP) on CNTs and its complexation with Ni ions, uniform coating of Ni nanoparticles on CNTs is well developed after it is introduced in the hydrothermal process. The prepared Ni/CNTs composites exhibited excellent MA performance in comparison with those of reported Ni/CNTs composites for the ideal impedance matching performance and microwave attenuation ability. When the filler content was only 15 wt%, the minimum reflection loss (RLmin) reached -39.5 dB, and the effective bandwidth (EB) with RL < -10 dB reached 5.2 GHz at the thickness of 1.15 mm. A scalable strategy of regulating the distribution of Ni nanoparticles and preparing a lightweight microwave absorber based on CNTs was developed in this study, which can serve as a vital guideline for preparing novel MA composite materials.

Plumbagin is a novel GPX4 protein degrader that induces apoptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, remains a global health challenge requiring novel and effective therapeutic agents and approaches. Here, we found that a natural product plumbagin can inhibit the growth of HCC cells by inducing the downregulation of GPX4, but not other antioxidant enzymes such as CAT, SOD1, and TXN. Functionally, genetic silence of GPX4 enhances, whereas the overexpression of GPX4 inhibits plumbagin-induced apoptosis (rather than ferroptosis) in HCC cells. Furthermore, GPX4 protein specifically binds the deubiquitinase USP31, but not other deubiquitinases such as CYLD, USP1, USP14, USP20, USP30, USP38, UCHL1, UCHL3, and UCHL5. As an inhibitor of deubiquitinating enzymes, especially USP31, plumbagin induces ubiquitination of GPX4 and subsequent proteasomal degradation of GPX4 in HCC cells. Accordingly, plumbagin-mediated tumor suppression is also associated with the downregulation of GPX4 and the upregulation of apoptosis in a subcutaneous xenograft tumor model. Taken together, these findings demonstrate a novel anticancer mechanism of plumbagin by inducing GPX4 protein degradation.

Diagnosis of cervical lymph node metastasis with thyroid carcinoma by deep learning application to CT images.

Introduction: The incidence of thyroid diseases has increased in recent years, and cervical lymph node metastasis (LNM) is considered an important risk factor for locoregional recurrence. This study aims to develop a deep learning-based computer-aided diagnosis (CAD) method to diagnose cervical LNM with thyroid carcinoma on computed tomography (CT) images. Methods: A new deep learning framework guided by the analysis of CT data for automated detection and classification of LNs on CT images is proposed. The presented CAD system consists of two stages. First, an improved region-based detection network is designed to learn pyramidal features for detecting small nodes at different feature scales. The region proposals are constrained by the prior knowledge of the size and shape distributions of real nodes. Then, a residual network with an attention module is proposed to perform the classification of LNs. The attention module helps to classify LNs in the fine-grained domain, improving the whole classification network performance. Results: A total of 574 axial CT images (including 676 lymph nodes: 103 benign and 573 malignant lymph nodes) were retrieved from 196 patients who underwent CT for surgical planning. For detection, the data set was randomly subdivided into a training set (70%) and a testing set (30%), where each CT image was expanded to 20 images by rotation, mirror image, changing brightness, and Gaussian noise. The extended data set included 11,480 CT images. The proposed detection method outperformed three other detection architectures (average precision of 80.3%). For classification, ROI of lymph node metastasis labeled by radiologists were used to train the classification network. The 676 lymph nodes were randomly divided into 70% of the training set (73 benign and 401 malignant lymph nodes) and 30% of the test set (30 benign and 172 malignant lymph nodes). The classification method showed superior performance over other state-of-the-art methods with an accuracy of 96%, true positive and negative rates of 98.8 and 80%, respectively. It outperformed radiologists with an area under the curve of 0.894. Discussion: The extensive experiments verify the high efficiency of the proposed method. It is considered instrumental in a clinical setting to diagnose cervical LNM with thyroid carcinoma using preoperative CT images. The future research can consider adding radiologists' experience and domain knowledge into the deep-learning based CAD method to make it more clinically significant. Conclusion: The extensive experiments verify the high efficiency of the proposed method. It is considered instrumental in a clinical setting to diagnose cervical LNM with thyroid carcinoma using preoperative CT images.

Copper-dependent autophagic degradation of GPX4 drives ferroptosis.

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly understood. Here, we report an unexpected role for copper in promoting ferroptotic cell death, but not cuproptosis, by inducing macroautophagic/autophagic degradation of GPX4. Copper chelators reduce ferroptosis sensitivity but do not inhibit other types of cell death, such as apoptosis, necroptosis, and alkaliptosis. Conversely, exogenous copper increases GPX4 ubiquitination and the formation of GPX4 aggregates by directly binding to GPX4 protein cysteines C107 and C148. TAX1BP1 (Tax1 binding protein 1) then acts as an autophagic receptor for GPX4 degradation and subsequent ferroptosis in response to copper stress. Consequently, copper enhances ferroptosis-mediated tumor suppression in a mouse model of pancreatic cancer tumor, whereas copper chelators attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into the link between metal stress and autophagy-dependent cell death.Abbreviations: CALCOCO2, calcium binding and coiled-coil domain 2; GPX4, glutathione peroxidase 4; MAP1LC3A/B, microtubule associated protein 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear receptor coactivator 4; OPTN, optineurin; PDAC, pancreatic ductal adenocarcinoma; RIPK1, receptor interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member 1; SQSTM1, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.

Deep learning-based immunohistochemical estimation of breast cancer via ultrasound image applications.

Background: Breast cancer is the key global menace to women's health, which ranks first by mortality rate. The rate reduction and early diagnostics of breast cancer are the mainstream of medical research. Immunohistochemical examination is the most important link in the process of breast cancer treatment, and its results directly affect physicians' decision-making on follow-up medical treatment. Purpose: This study aims to develop a computer-aided diagnosis (CAD) method based on deep learning to classify breast ultrasound (BUS) images according to immunohistochemical results. Methods: A new depth learning framework guided by BUS image data analysis was proposed for the classification of breast cancer nodes in BUS images. The proposed CAD classification network mainly comprised three innovation points. First, a multilevel feature distillation network (MFD-Net) based on CNN, which could extract feature layers of different scales, was designed. Then, the image features extracted at different depths were fused to achieve multilevel feature distillation using depth separable convolution and reverse depth separable convolution to increase convolution depths. Finally, a new attention module containing two independent submodules, the channel attention module (CAM) and the spatial attention module (SAM), was introduced to improve the model classification ability in channel and space. Results: A total of 500 axial BUS images were retrieved from 294 patients who underwent BUS examination, and these images were detected and cropped, resulting in breast cancer node BUS image datasets, which were classified according to immunohistochemical findings, and the datasets were randomly subdivided into a training set (70%) and a test set (30%) in the classification process, with the results of the four immune indices output simultaneously from training and testing, in the model comparison experiment. Taking ER immune indicators as an example, the proposed model achieved a precision of 0.8933, a recall of 0.7563, an F1 score of 0.8191, and an accuracy of 0.8386, significantly outperforming the other models. The results of the designed ablation experiment also showed that the proposed multistage characteristic distillation structure and attention module were key in improving the accuracy rate. Conclusion: The extensive experiments verify the high efficiency of the proposed method. It is considered the first classification of breast cancer by immunohistochemical results in breast cancer image processing, and it provides an effective aid for postoperative breast cancer treatment, greatly reduces the difficulty of diagnosis for doctors, and improves work efficiency.

The deubiquitinating enzyme STAMBP is a newly discovered driver of triple-negative breast cancer progression that maintains RAI14 protein stability.

Triple-negative breast cancer (TNBC) is a heterogeneous malignancy in women. It is associated with poor prognosis, aggressive malignant behavior, and limited treatment options. In the ubiquitin‒proteasome system (UPS), deubiquitinases (DUBs) are potential therapeutic targets for various tumors. In this study, by performing unbiased siRNA screening, we identified STAMBP, a JAMM metalloprotease in the DUB family, as a driver of human TNBC tumor growth. Functionally, the knockdown of STAMBP inhibited the proliferation, migration, and invasion of multiple TNBC cell lines. Immunoprecipitation-mass spectrometry combined with functional and morphological analysis verified the interaction between STAMBP and the actin-binding protein RAI14. Mechanistically, STAMBP stabilized the RAI14 protein by suppressing the K48-linked ubiquitination of RAI14 and thus prevented its proteasomal degradation. Therefore, knocking down STAMBP resulted in the reduction in RAI14 protein levels and suppression of tumor growth in vitro and in vivo. Importantly, high levels of STAMBP were correlated with poor prognosis in TNBC patients. In summary, we reveal a previously unrecognized DUB pathway that promotes TNBC progression and provides a rationale for potential therapeutic interventions for the treatment of TNBC.

Effect of marigold (Tagetes erecta L.) on soil microbial communities in continuously cropped tobacco fields.

Root-knot nematode disease is a catastrophic soil-borne disease in tobacco production. The regulation of natural microbial communities is considered a good disease management approach to suppress the incidence of soilborne diseases. In this study, the effects of tobacco (Nicotiana tabacum L.)-marigold (Tagetes erecta L.) rotation on the diversity and structure of soil microbial communities in continuously cropped tobacco fields were analyzed to manage this devastating pathogen. The results showed that the soil bacterial OTUs increased after marigold rotation and that the bacterial Shannon, ACE, Chao1 index, and fungal Shannon index were higher in the tobacco-marigold rotation fields than in the continuously cropped tobacco fields by 3.98%, 10.37%, 5.46%, and 3.43%, respectively. After marigold rotation, the relative abundances of Actinobacteria, Acidobacteria, and Ascomycota increased by 28.62%, 107.50%, and 57.44%, respectively, and the proportion of beneficial bacterial genera such as Nocardioides, Gemmatimonas, and Bradyrhizobium increased. In addition, our results also showed that rotation of marigold could effectively reduce the incidence of root-knot nematodes in the next crop of tobacco. These results indicate that marigold rotation had a positive effect on the soil microecological environment of continuously cropped tobacco fields, reducing the obstacles to continuous cropping of tobacco.

Evaluation of intracoronary function after reduction of ventricular rate by esmolol in severe stenotic myocardial bridge: A case report.

BACKGROUND: Severe stenotic myocardial bridges (MBs) have been reported to lead to intracoronary ischaemia, but the physiological evaluation of MBs using intracoronary function evaluation indicators after intraoperative drug treatment has not been fully established. CASE SUMMARY: We performed through snuff fossa for coronary angiography in a patient with chest tightness after repeated exercise, and the results showed that the middle part of the anterior descending branch was a MB with 100% systolic compression. The intracoronary function evaluation (defined as the ratio of distal coronary pressure to aortic pressure with zero microcirculation resistance) was instantaneous wave-free ratio (IFR) without drug and fractional flow reserve (FFR) with adenosine. The IFR was 0.73, and the FFR was 0.66. Then esmolol 0.02 µg/kg/min was intravenously injected. The IFR and FFR were measured again when the heart rate dropped to 60 beats/min. The IFR was 0.83, and the FFR 0.65. CONCLUSION: This case report is a case of isolated MB with severe stenosis. After intraoperative drug treatment decreased the ventricular rate, an increase in the coronary function evaluation index was immediately observed to confirm the effective improvement of coronary blood flow.

Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells.

OBJECTIVE: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC. METHODS: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts. RESULTS: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3ß and subsequent downstream MCL-1 degradation. CONCLUSIONS: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatmen.

Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 µM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg-1 · d-1, ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 µM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

Construction of a TRFIC strip for rapid and sensitive detection of Ralstoniasolanacearum.

The development of a sensitive and rapid screening method for Ralstonia solanacearum is critical for the control of tobacco wilt. In the present study, tissue homogenates of three tobacco varieties (Honda, Yunnan 87 and K326) with different resistance to R. solanacearum, were individually used as additives to the bacteria culture medium. The changes in R. solanacearum secretome were investigated and one of the most abundant secretary proteins with increased expression, polygalacturonase (PG), was selected as a marker for R. solanacearum identification. Then PG gene was cloned into E. coli, and the expressed protein was used as the immunogen to develop monoclonal antibodies. Subsequently, the monoclonal antibody against PG was coupled with synthesized polystyrene microspheres, and a rapid test strip system was developed for the detection of R. solanacearum based on time-resolved fluorescent immunochromatographic (TRFIC) method. Under optimal conditions, the detection limit of the strips could reach 72 cells/mL; while it was 422 cells/mL with a linear range from 4 × 102 to 5.12 × 104 cells/mL when testing tobacco samples, which is 1000 times lower than that of colloidal gold-labeled strips. Notably, no cross-reactivity was observed with nine tobacco-related pathogens. Finally, this TRFIC strips was applied to detect R. solanacearum existed in the tobacco and soils of fields with or without bacterial wilt. The results demonstrated that this TRFIC strips could distinguish the difference in bacterial concentration existed in tobacco and soil between the two fields. In summary, this test strip is suitable for sensitive, quick screening of R. solanacearum in tobacco.

Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30.

Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells.

Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.

Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death.

Ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are two major systems for protein quality control (PQC) in eukaryotic cells. Interconnectivity between these two pathways has been suggested, but the molecular detail of how they impact each other remains elusive. Proteasomal deubiquitinase (DUB) is an important constituent in the UPS and has proved to be a novel anticancer target. We have previously found that a novel DUB inhibitor, nickel complex NiPT, induces apoptosis in both cultured tumor cell lines and cancer cells from acute myeloid leukemia human patients. In this study, we found that NiPT triggered autophagy both in vitro and in vivo. Mechanistically, NiPT targets two DUBs, USP14, and UCHL5, and increased the total cellular level of polyubiquitination. Deletion of the Ubiquitin Associated (UBA) domain of P62 that is required for polyubiquitin binding prevented NiPT-induced autophagy. NiPT-induced autophagy is through either concomitant activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) signaling, or eliciting endoplasmic reticulum (ER)-stress by activating activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Moreover, NiPT could induce more lung cancer cells undergoing apoptosis if it synergistically uses autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cell from death. Collectively, our findings demonstrate that autophagy inhibition enhances the anticancer effects of proteasomal DUB inhibitor and might be an effective treatment strategy for lung cancer.

Association between the location of transposed ovary and ovarian dose in patients with cervical cancer treated with postoperative pelvic radiotherapy.

BACKGROUND AND PURPOSE: How to protect the ovarian function during radiotherapy is uncertain. The purpose of this study was to explore the association between the location of the transposed ovary and the ovarian dose in patients with cervical cancer received radical hysterectomy, ovarian transposition, and postoperative pelvic radiotherapy. METHODS: A retrospective analysis was conducted of 150 young patients with cervical cancer who received radical hysterectomy, intraoperative ovarian transposition, and postoperative adjuvant radiotherapy in Zhejiang Cancer Hospital. Association between location of the transposed ovaries and ovarian dose was evaluated. The transposed position of ovaries with a satisfactory dose was explored using a receiver operator characteristic curve (ROC) analysis. Patients' ovarian function was followed up 3 months and 1 year after radiotherapy. RESULTS: A total of 32/214 (15%) transposed ovaries were higher than the upper boundary of the planning target volume (PTV). The optimum cutoff value of > 1.12 cm above the iliac crest plane was significantly associated with ovaries above the upper PTV boundary. When the ovaries were below the upper boundary of PTV, the optimum cutoff value of transverse distance > 3.265 cm between the ovary and PTV was significantly associated with ovarian max dose (Dmax) ≤ 4Gy, and the optimum cutoff value of transverse distance > 2.391 cm was significantly associated with ovarian Dmax≤5Gy. A total of 77 patients had received complete follow-up, and 56 patients (72.7%) showed preserved ovarian function 1 year after radiotherapy, which was significantly increased compared with 3 months (44.2%) after radiotherapy. CONCLUSIONS: The location of transposed ovaries in patients with cervical cancer is significantly correlated with ovarian dose in adjuvant radiotherapy. We recommend transposition of ovaries > 1.12 cm higher than the iliac crest plane to obtain ovarian location above PTV. When the transposed ovary is below the upper boundary of PTV, ovarian Dmax ≤4Gy may be obtained when the transverse distance between the ovary and PTV was > 3.265 cm, and the ovarian Dmax≤5Gy may be obtained when the transverse distance was > 2.391 cm.

Prognostic value of the 2018 FIGO staging system for cervical cancer patients with surgical risk factors.

Objective: To determine the predictive value of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer patients with surgical risk factors. Methods: Data of 662 cervical cancer patients (stages IB and IIA) with surgical risk factors treated at Zhejiang Cancer Hospital between 2008 and 2011 were retrospectively reviewed. Univariate log-rank test and multivariate Cox regression models were adopted to evaluate the relationship between 2018 FIGO stage and survival. Results: On re-staging of patients, 17.3%, 44.5%, 25.4%, and 37.1% of the patients with FIGO 2009 stage IB1, IB2, IIA1, and IIA2, respectively, were upgraded to FIGO 2018 IIIC1P stage, and 2.1%, 3.0%, 3.1%, and 2.1% patients, respectively, were upgraded to IIIC2P stage. The 5-year overall survival (OS) rates of patients with FIGO 2018 stage IB1, IB2, IB3, IIA1, IIA2, IIIC1P, and IIIC2P were 95.3%, 95.1%, 90.4%, 92.4%, 86.4%, 81.9%, and 56.3%, respectively. The 5-year progression-free survival (PFS) rates were 94.0%, 91.0%, 88.5%, 91.4%, 86.4%, 79.5%, and 43.8%, respectively. The 5-year OS rates of patients with 1-2 positive pelvic lymph nodes (PLNs) and those with >2 positive PLNs were 86.0% and 73.7%, respectively, and the 5-year PFS rates were 84.2% and 70.2%, respectively. OS and PFS of patients with 1-2 positive PLNs in stage IIIC1P were similar to those of patients in stage IIA2 without lymph node metastasis, but significantly better than those of patients with >2 positive PLNs. Multivariate analysis showed FIGO 2018 stage to be an independent prognostic factor for OS and PFS. Conclusion: The 2018 FIGO staging system for cervical cancer appears to be useful for predicting prognosis of patients with risk factors after radical surgery. Survival of stage IIA1 patients is better than that of stage IB3 patients. Stage IIIC1 is not homogenous; survival in stage IIIC1P depends on the number of positive PLNs.

A comprehensive analysis of the factors of positive pelvic lymph nodes on survival of cervical cancer patients with 2018 FIGO stage IIIC1p.

Objective: To evaluate the factors associated with positive pelvic lymph nodes (LNs) on the survival of patients with 2018 FIGO stage IIIC1p cervical cancer. Methods: We retrospectively analyzed 155 patients with pelvic lymph node metastasis (LNM) confirmed by pathology after radical resection of cervical cancer treated at Zhejiang Cancer Hospital, China, between March 2008 and October 2011. We analyzed the influence of the factors associated with positive pelvic LNs on the survival of patients. Results: The 5-year progress-free survival (PFS) and overall survival (OS) of patients were 78.1% and 81.9%, respectively. The 5-year PFS and OS of patients with more than 2 LNM were worse compared with patients with 1 or 2 LNM (68.4% vs 83.7%, p=0.013; 72.4% vs 87.6%, p=0.017, respectively). The 5-year PFS and OS of patients with more than 2 LNM sites were worse than that of patients with 1 or 2 LNM sites (60.0% vs 82.4%, p=0.008; 70.0% vs 84.8%, p=0.045, respectively). The 5-year PFS and OS of patients with common iliac LNM was poorer than that of patients without common iliac LNM (60.7% vs 81.9%, p=0.008; 67.9% vs 85.0%, p=0.020, respectively). Compared with other patients, the survival of patients with these three factors (more than 2 LNM, more than 2 LNM sites, and common iliac LNM) was the worst (p<0.05). Conclusion: More than 2 LNM, more than 2 LNM sites, and common iliac LNM were predictive factors of poor survival in stage IIIC1p cervical cancer patients. Survival of patients with stage IIIC1p cervical cancer declined with increasing presence of such factors. The combined evaluation of the factors associated with positive pelvic LNs is a more comprehensive and pragmatic approach in evaluating the prognosis of cervical cancer.