A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Dual-Responsive Supramolecular Polymeric Nanomedicine for Self-Cascade Amplified Cancer Immunotherapy.

Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long-term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) to self-cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by ß-cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, and self-assembled through host-guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO-triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

Discovery of benzyloxy benzamide derivatives as potent neuroprotective agents against ischemic stroke.

Aberrant activation of N-methyl-d-aspartate receptors (NMDAR) and the resulting neuronal nitric oxide synthase (nNOS) excessive activation play crucial pathogenic roles in neuronal damage caused by stroke. Disrupting postsynaptic density protein 95 (PSD95)-nNOS protein-protein interaction (PPI) has been proposed as a potential therapeutic strategy for ischemic stroke without incurring the unwanted side effects of direct NMDAR antagonism. Based on a specific PSD95-nNOS PPI inhibitor (SCR4026), we conducted a detailed study on structure-activity relationship (SAR) to discover a series of novel benzyloxy benzamide derivatives. Here, our efforts resulted in the best 29 (LY836) with improved neuroprotective activities in primary cortical neurons from glutamate-induced damage and drug-like properties. Whereafter, co-immunoprecipitation experiment demonstrated that 29 significantly blocked PSD95-nNOS association in cultured cortical neurons. Furthermore, 29 displayed good pharmacokinetic properties (T1/2 = 4.26 and 4.08 h after oral and intravenous administration, respectively) and exhibited powerful therapeutic effects in rats subjected to middle cerebral artery occlusion (MCAO) by reducing infarct size and neurological deficit score. These findings suggested that compound 29 may be a promising neuroprotection agent for the treatment of ischemic stroke.

Laboratory indices in patients with osteonecrosis of the femoral head: a retrospective comparative study.

BACKGROUND: Osteonecrosis of the femoral head is a degenerative condition linked to corticosteroids, alcoholism, or trauma. With its rising prevalence due to increased hormone drug use and its debilitating effects on young to middle-aged individuals, understanding its association with specific laboratory indicators can aid early diagnosis and prevention. METHODS: Upon retrospective analysis of the clinical data pertaining to individuals diagnosed with femoral head necrosis, spanning from January 2016 to January 2022, a comprehensive evaluation was conducted within the same time frame. The study aimed to ascertain the presence of femoral head necrosis in a total of 1176 individuals. A total of 1036 healthy patients were recruited randomly, ensuring that their ages matched. The risk variables associated with the utilization of logistic regression analysis and analysis techniques are employed. The patient examines the age distribution within a specific age group. RESULTS: The levels of high-density lipoprotein, low-density lipoprotein A1, lipoprotein B1, total protein, albumin, globulin, and other lipophilic metabolism and coagulation markers exhibited a statistically significant increase compared to the control group. A multifactor logistic regression analysis was conducted to identify potential risk factors associated with femoral head necrosis in patients. CONCLUSION: Femoral head necrosis is associated with a range of variables including coagulation malfunction, lipid metabolic abnormalities, and inflammation.

A Mitochondria-Targeted NIR-II AIEgen Induced Pyroptosis for Enhanced Tumor Immunotherapy.

Cancer immunotherapy is a favorable strategy for facilitating anti-tumor immunity, but it shows limited benefits in clinical practice owing to the immunosuppressive tumor microenvironment. Pyroptosis shows great immunostimulatory effect on tumor, whereas the lack of pyroptotic inducer with imaging property has restricted its progress in tumor theranostics. Herein, a mitochondria-targeted aggregation-induced emission (AIE) luminogen (TPA-2TIN) with NIR-II emission is designed for highly efficient induction of tumor cell pyroptosis. The fabricated TPA-2TIN nanoparticles can be efficiently taken up by tumor cells and selectively accumulated in tumor for a long term observed by NIR-II fluorescence imaging. More importantly, the TPA-2TIN nanoparticles can effectively stimulate immune responses both in vitro and in vivo mediated by the mitochondrial dysfunctions and the subsequent activation of the pyroptotic pathway. Ultimately, the reversal of the immunosuppressive tumor microenvironment significantly enhances the immune checkpoint therapy. This study paves a new avenue for adjuvant immunotherapy of cancer.

Adjuvant therapy for cholangiocarcinoma after surgery and prognosis factors for cholangiocarcinoma: A single-center retrospective cohort study.

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignant tumor, and more than 60% of patients have recurrence and metastasis after surgery. The efficacy of postoperative adjuvant therapy for CCA remains unclear. This study aimed to explore whether adjuvant therapy benefits patients with CCA and examine the independent prognostic factors for overall survival (OS) and progression-free survival (PFS). Methods: Patients with CCA undergoing surgery were retrospectively enrolled in this study from June 2016 to June 2022. The chi-square test or Fisher exact test was used to analyze the correlation between clinicopathologic characteristics. Survival curves were plotted using the Kaplan-Meier method, and the Cox regression model was used for univariate and multivariate analysis to search for independent prognostic factors. Results: Of the 215 eligible patients, 119 patients received adjuvant therapy, and the other 96 patients did not. The median follow-up was 37.5 months. The median OS of CCA patients with and without adjuvant therapy was 45 and 18 months (P < 0.001), respectively. The median PFS of CCA patients with and without adjuvant therapy was 34 and 8 months (P < 0.001), respectively. The Cox univariate and multivariate regression analysis showed that preoperative aspartate transaminase and carbohydrate antigen 19-9, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for OS (all P values < 0.05). Preoperative carbohydrate antigen 125, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for PFS (all P values < 0.05). The stratified analysis by TMN stage detected significant differences in the early stages (median OS [mOS]: P = 0.0128; median PFS [mPFS]: P = 0.0209) and advanced stages (mOS and mPFS: both P values < 0.001). Adjuvant therapy was also identified as a significantly favorable prognostic factor for OS and PFS in the early stages and advanced stages. Conclusion: Postoperative adjuvant therapy can improve the prognosis of patients with CCA, even in the early stages and advanced stages. All data suggest that adjuvant therapy should be incorporated into the treatment of CCA in all cases, where appropriate.

Recent Development of Supramolecular Cancer Theranostics Based on Cyclodextrins: A Review.

With the development of personalized medical demands for precise diagnosis, rational management and effective cancer treatment, supramolecular theranostic systems have received widespread attention due to their reversibly switchable structures, sensitive response to biological stimuli and integration ability for multiple capabilities in a single platform with a programmable fashion. Cyclodextrins (CDs), benefiting from their excellent characteristics, such as non-toxicity, easy modification, unique host-guest properties, good biocompatibility, etc., as building blocks, serve as an all-purpose strategy for the fabrication of a supramolecular cancer theranostics nanodevice that is capable of biosafety, controllability, functionality and programmability. This review focuses on the supramolecular systems of CD-bioimaging probes, CD-drugs, CD-genes, CD-proteins, CD-photosensitizers and CD-photothermal agents as well as multicomponent cooperation systems with regards to building a nanodevice with functions of diagnosis and (or) therapeutics of cancer treatment. By introducing several state-of-the-art examples, emphasis will be placed on the design of various functional modules, the supramolecular interaction strategies under the fantastic topological structures and the hidden "bridge" between their structures and therapeutic efficacy, aiming for further comprehension of the important role of a cyclodextrin-based nanoplatform in advancing supramolecular cancer theranostics.

Mitochondrial-Targeted Delivery of Polyphenol-Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases.

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.

Pain catastrophizing and associated factors in preoperative total knee arthroplasty in Lanzhou, China: a cross-sectional study.

BACKGROUND: Pain catastrophizing in preoperative total knee arthroplasty (TKA) patients is associated with several poorly characterised factors in the literature. This study investigated the current state and associated factors of preoperative pain catastrophizing in patients undergoing TKA. METHODS: This descriptive cross-sectional study was conducted at the orthopedics ward of two tertiary hospitals in Lanzhou, China. Pain catastrophizing was measured using the Chinese versions of the Pain Catastrophizing Scale, Short Form-36 (physical function domain), Numerical Rating Scale, Oxford Knee Score, Hospital Anxiety and Depression Scale, and Life Orientation Test-Revised. RESULTS: The study included 360 participants. Preoperative TKA pain catastrophizing in all patients was high, with a mean score of 24.92 (SD: 12.38). The stepwise multiple linear regression analysis revealed anxiety (ß = 0.548, P < 0.01), education level (ß = - 0.179, P < 0.01), physical function (ß = - 0.156, P < 0.01), and pain intensity during activity (ß = 0.105, P = 0.015) as associated factors for pain catastrophizing, possibly explaining 51.2% of the total variation (F = 95.149, P < 0.01). CONCLUSION: Anxiety was the most relevant factor for pain catastrophizing in patients with preoperative TKA. Lower education levels, poor physical function, and stronger pain intensity during the activity were also associated with pain catastrophizing.

An NIR Discrete Metallacycle Constructed from Perylene Bisimide and Tetraphenylethylene Fluorophores for Imaging-Guided Cancer Radio-Chemotherapy.

To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.

[Treatment of senile lumbar spinal stenosis by unilateral approach and bilateral decompression with large channel endoscopy].

OBJECTIVE: To evaluate clinical effect of unilateral approach and bilateral decompression via large channel endoscopic system for the treatment of lumbar spinal stenosis. METHODS: The clinical data of 32 patients with lumbar spinal tenosis treated by unilateral approach and bilateral decompression via large channel endoscopy from February 2018 to February 2019 were retrospectively analyzed. There were 18 males and 14 females, aged 65 to 84 years old with an average of (70.6± 8.4) years. The course of disease was from 1 to 12 years. All 32 cases were accompanied by numbness or pain in the lower limbs, of which 28 cases were accompanied by intermittent claudication. Narrow segments were L3, 4 of 2 cases, L4, 5 of 19 cases, L5S1 of 13 cases, including double segments of 2 cases. Preoperative imaging showed 3 cases of central canal stenosis, 21 cases of bilateral lateral recess stenosis and 8 cases of mixed stenosis. Operation time and complications were recorded. X-ray, CT and MRI were analyzed at 3 days, 3 months and 1 year after operation. Visual analogue scale(VAS), Oswestry Disability Index (ODI), single continuous walking distance(SCWD) were observed before and after operation. Modified Macnab standard were used to evaluate the clinical effect at 1 year after operation. RESULTS: All the patients were followed up for 12-24 (17.68±2.43) months and all operations were successfully completed with the operation time of 70-160(85.64±11.94) min. Spinal dural tear occurred in 1 case during the operation, and sensory disturbance in the other side of lower limb in a short period of time occurred in 2 cases, all improved after corresponding treatment. Postoperative imaging showed that the spinal canal was significantly enlarged and the nerve root was fully released. Before operation and 3 days, 3 months, 1 year after operation, VAS scores of low back pain were 4.62 ±1.41, 2.73 ±1.35, 1.21 ±1.17, 1.11 ±0.34, respectively;VAS scores of leg pain were 6.83 ± 1.71, 3.10±1.50, 1.08±0.19, 0.89±0.24, respectively. VAS scores of low back pain and leg pain each time point after operation were obvious improved (P<0.05); there was significant difference between 3 months and 3 days after operation(P<0.05), and there was no significant difference between 3 months and 1 year after operation (P>0.05). Before operation and 3 days, 3 months, 1 year after operation, ODI scores were 38.40 ±6.48, 18.42 ±2.40, 5.48 ±0.77, 3.05 ±0.28, respectively; SCWD was (47.48±5.32) m, (52.89±11.23) m, (245.43±18.94) m, (468.97±55.87) m, respectively. The differences in ODI score and SCWD postoperative time points were statistically significant compared with those before operation (P<0.05). The difference between 3 months and 3 days after operation was statistically significant (P<0.05). The difference between 1 year and 3 months after operation was statistically significant (P<0.05). According to Macnab standard to evaluate clinical effect at 1 year after operation, 15 cases got excellent results, 14 good, 3 fair. CONCLUSION: It is a safe and effective way to treat lumbar spinal stenosis with unilateral approach and bilateral decompression via large channel endoscopic system. It has the advantages of sufficient decompression, less trauma, fast recovery, high safety and low incidence of postoperative complications. It can minimize the damage to the stable structure of the lumbar spine and is an ideal minimally invasive operation for the treatment of lumbar spinal stenosis.

Posterior percutaneous endoscopic versus traditional surgery for cervical disc herniation: A protocol for systematic review and meta analysis.

BACKGROUND: Posterior percutaneous endoscopic cervical diskectomy (P-PECD) can be used posterior microdiscectomy for cervical disc herniation. But only some small sample sizes of clinical studies have evaluated the efficacy and safety of P-PECD. This study aim to evaluated the efficacy and safety of P-PECD compared with traditional open surgery. METHODS: We will search the following seven electronic databases from their initiation to the May 1, 2020: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM) and Wanfang database. All randomized controlled trials, non-randomized controlled trials and retrospective case controls that compared the efficacy and safety of P-PECD and traditional open surgery in the treatment of cervical disc herniation will be included. The pooled odds ratio with 95% credible intervals (CIs) was used for the dichotomous variables. The mean difference with 95% CIs was used for the continuous variables. All analyses were conducted by Comprehensive Meta Analysis 2.0. A 2-tailed P value < 0.05 is considered statistically significant. RESULTS: The results of systematic review and meta-analysis will be submitted to a peer-reviewed journal. CONCLUSION: Our study will provide clarity regarding for clinicians to choices best surgical approach for patients with cervical disc herniation. Any changes that need to be made during the process of this study will be explained in the final full-text publication. PROTOCOL REGISTRATION NUMBER: CRD42020164011.

[Transforaminal percutaneous endoscopic lumbar discectomy combined with anchorage technique of pedicle for the treatment of high prolapse free lumbar disc herniation].

OBJECTIVE: To investigate the clinical effects of percutaneous spinal endoscopy (percutaneous endoscopy) in the treatment of high prolapse free lumbar disc herniation. METHODS: From May 2016 to June 2018, 24 patients with highly prolapse free lumbar disc herniation were enrolled in this study, including 11 males and 13 females, ranging in age from 48 to 72 years old, with an average of (59.5±7.2) years old. There were 1 case of L2, 3, 5 cases of L3, 4, 18 cases of L4, 5. The course of disease ranged from 8 to 26 months, with an average of (16.2±6.3) months. All the patients were subjected to local infiltration anesthesia. The clinical outcomes were evaluated by visual analog scale (VAS) for leg pain, low backpain and Oswestry Disability Index (ODI) at preoperative, first day after operation and 6 month after surgery. All data were statisticed by SPSS 22.0. RESULTS: All the patients were followed up, and the duration ranged from 12 to 24 months, with a mean of (17.5±5.3) months. The average operation time was(69.8±14.2) minutes. One patient had cerebrospinal fluid leakage, which improved after supine rest. VAS scores of lower back pain were 6.36±1.27, 3.94±1.03, 1.62±0.87, 0.44±0.27, 0.37±0.29. VAS scores of leg pain were 8.28±1.74, 3.16±1.24, 2.83±1.13, 0.83±0.31, 0.46±0.31, and the differences were statistically significant (P<0.05). The ODI were (48.79±9.83)%, (36.51±11.24)%, (21.05±6.35)%, (9.83±4.62)% and (7.24±4.72)% 1 day before and 1 weeks, 3 months, 6 months and 1 year after the operation, respectively. One year after the operation, the modified Macnab evaluation system was used to evaluate the clinical efficacy of the patients, 19 patients got an excellent result, 3 good, 2 fair and 0 poor. CONCLUSION: Percutaneous endoscopic pedicle anchoring technique for the treatment of high prolapse free lumbar disc herniation can effectively improve the clinical symptoms of patients, and has the advantages of less trauma, less bleeding, rapid recovery, complete removal of the nucleus pulposus, and less pain of patients, etc., its clinical efficacy is accurate, operability is strong, it is worth promoting in the clinical use.

[Long non-coding RNA for metabolism of bone tissue].

The mechanism of metabolism of bone and cartilage are one of focus of orthopedic knowledge, and its clinical and basic study plays an important role in preventing and treating osteoporosis, degeneration of bone and joint, bone tumor. At present, the mechanism of metabolism of bone and cartilage studied from protein, signal pathway to mRNA transcription factor regulation. As a new regulatory factor for non-coding proteins, long non-coding RNA(LncRNA) participates in physiological and pathological process. In recent years, a large number of researche showed that LncRNA plays an important role in metabolism of bone and cartilage, and proved LncRNA participates in development and conversion of bone metabolism. With the exposure of function chennel and target of LncRNA, the key role of LncRNA in bone metabolism were proved constantly. The paper concluded biological characteristics of LncRNA, function and target spot of LncRNA in bone and cratilage metabolism, and in further state gene regulatory mechanism of bone and cartilage metabolism, explore diagnosis and treatment, provide new thought and treatment target for bone metabolism.

[Investigations and analysis of traumatic condition of Longnan area in Wenchuan earthquake].

OBJECTIVE: To investigate and analyze the traumatic conditions of Longnan area of Gansu in Wenchuan earthquake, and to explore the measures coping with unexpected disasters. METHODS: A sample survey including questionnaire survey, interviews and other methods was adopted to investigate the conditions of affected population of Longnan area in earthquake, especially on the traumatic conditions, the injured causes, treatment methods. RESULTS: In the sample survey of a total of 1652 earthquake casualties, the dead were 16 and the patients with extremities fractures were 750 (45.4%). Organized and timely rescue of the wounded could reduce the complications and the mortality . CONCLUSION: Strengthening the prevention and treatment of earthquake trauma can effectively decrease the death rate and disabled rate.