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Abstract Background Omadacycline is a new generation of tetracycline antibiotics, and its clinical application is increasing. We report the first case of acute pancreatitis possibly induced by omadacycline. Case presentation The patient was admitted to the emergency intensive care unit due to community-acquired pneumonia. The initial treatment consisted of meropenem combined with levofloxacin, and the regimen was subsequently switched to omadacycline combined with cefoperazone/sulbactam due to sputum culture showing carbapenem-resistant Acinetobacter baumannii. Seven days after the administration of omadacycline, abdominal tenderness occurred, and CT scan revealed an enlarged gallbladder with exudation from the pancreatic head. The patient was diagnosed with acute pancreatitis and improved after dis-continuing omadacycline. Conclusions Omadacycline, like other tetracycline antibiotics, may cause pancreatitis. Combination medications can be an important factor in this adverse reaction.

Abstract Background Oritavancin is a new generation of semi-synthetic glycopeptide antibiotics against Gram-positive bacteria, which served as the first and only antibiotic with a single-dose therapeutic regimen to treat ABSSSI. A naturally occurring glycopeptide A82846B is the direct precursor of oritavancin. However, its application has been hampered by low yields and homologous impurities. This study established a multi-step combinatorial strategy to rationally construct a high-quality and high-efficiency biosynthesis system for A82846B and systematically optimize its fermentation process to break through the bottleneck of microbial fermentation production. Results Firstly, based on the genome sequencing and analysis, we deleted putative competitive pathways and constructed a better A82846B-producing strain with a cleaner metabolic background, increasing A82846B production from 92 to 174 mg/L. Subsequently, the PhiC31 integrase system was introduced based on the CRISPR-Cas12a system. Then, the fermentation level of A82846B was improved to 226 mg/L by over-expressing the pathway-specific regulator StrR via the constructed PhiC31 system. Furthermore, overexpressing glycosyl-synthesis gene evaE enhanced the production to 332 mg/L due to the great conversion of the intermediate to target product. Finally, the scale-up production of A82846B reached 725 mg/L in a 15 L fermenter under fermentation optimization, which is the highest reported yield of A82846B without the generation of homologous impurities. Conclusion Under approaches including blocking competitive pathways, inserting site-specific recombination system, overexpressing regulator, overexpressing glycosyl-synthesis gene and optimizing fermentation process, a multi-step combinatorial strategy for the high-level production of A82846B was developed, constructing a high-producing strain AO-6. The combinatorial strategies employed here can be widely applied to improve the fermentation level of other microbial secondary metabolites, providing a reference for constructing an efficient microbial cell factory for high-value natural products.

Abstract Lung cancer (LC) is the leading cause of cancer‐related mortality worldwide. Radiotherapy is the main component of LC treatment; however, its efficacy is often limited by radioresistance development, resulting in unsatisfactory clinical outcomes. Here, we found that LC radiosensitivity is up‐regulated by decreased expression of long‐chain acyl‐CoA synthase 6 (ACSL6) after irradiation. Deletion of ACSL6 results in significant elevation of Friend leukemia integration 1 transcription factor (FLI1) and a marked decline of collagens (COLs). Blocking of ACSL6 impairs the tumor growth and upregulates FLI1, which reduces the levels of COLs and compromises irradiation‐induced autophagy, leading to considerable therapeutic benefits during radiotherapy. Moreover, the direct interaction between ACSL6 and FLI1 and engagement between FLI1 and COLs indicates the involvement of the ACSL6‐FLI1‐COL axis. Finally, the potently adjusted autophagy flux reduces its otherwise contributive capability in surviving irradiation stress and leads to satisfactory radiosensitization for LC radiotherapy. These results demonstrate that enhanced ACSL6 expression promotes the aggressive performance of irradiated LC through increased FLI1‐COL‐mediated autophagy flux. Thus, the ACSL6‐FLI1‐Col‐autophagy axis may be targeted to enhance the radiosensitivity of LC and improve the management of LC in radiotherapy.

Abstract Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

The lack of effective diagnostic and therapeutic techniques is a crucial cause of the high clinical mortality for malignancy. Notably, self-propelled micro/nanomotors are expected to address the drawbacks of conventional nanoparticles in tumor diagnosis and therapy. The special locomotion property ensures the high efficiency of micro/nanomotors in term of rapid distribution, deep penetration, and targeted delivery. Hence, in this review, the motion mechanism and the controllability of speed and direction of the micro/nanomotors were described, as well as the advantages regarding the enhancement of biological barrier crossing (overcoming blood flow obstacles, tumor microenvironment barriers), targeting delivery and deep penetration in the tumor. The most recent advances in micro/nanomotor contributions were comprehensively summarized to various medical imaging technologies, biosensing techniques, and therapeutic approaches, especially for the combination therapy and integration of diagnosis and treatment based on multifunctional micro/nanomotors. Furthermore, challenges for developing practical micro/nanomotors were discussed along with future directions from the clinicians' perspective, which is promised to speed up the clinical translation process and contribute to efficient tumor diagnosis and therapy.

Abstract Background To demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial. Methods We consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics. Results Compared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent. Conclusions The proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.

Abstract Background The process of initiating and completing clinical drug trials in hospital settings is highly complex, with numerous institutional, technical, and record-keeping barriers. In this study, we independently developed an integrated clinical trial management system (CTMS) designed to comprehensively optimize the process management of clinical trials. The CTMS includes system development methods, efficient integration with external business systems, terminology, and standardization protocols, as well as data security and privacy protection. Methods The development process proceeded through four stages, including demand analysis and problem collection, system design, system development and testing, system trial operation, and training the whole hospital to operate the system. The integrated CTMS comprises three modules: project approval and review management, clinical trial operations management, and background management modules. These are divided into seven subsystems and 59 internal processes, realizing all the functions necessary to comprehensively perform the process management of clinical trials. Efficient data integration is realized through extract-transform-load, message queue, and remote procedure call services with external systems such as the hospital information system (HIS), laboratory information system (LIS), electronic medical record (EMR), and clinical data repository (CDR). Data security is ensured by adopting corresponding policies for data storage and data access. Privacy protection complies with laws and regulations and de-identifies sensitive patient information. Results The integrated CTMS was successfully developed in September 2015 and updated to version 4.2.5 in March 2021. During this period, 1388 study projects were accepted, 43,051 electronic data stored, and 12,144 subjects recruited in the First Affiliated Hospital, Zhejiang University School of Medicine. Conclusion The developed integrated CTMS realizes the data management of the entire clinical trials process, providing basic conditions for the efficient, high-quality, and standardized operation of clinical trials.

Abstract Currently, there are no effective therapies for intestinal and hepatic fibrosis representing a considerable unmet need. Breakthroughs in pathogenesis have accelerated the development of anti‐fibrotic therapeutics in recent years. Particularly, with the development of nanotechnology, the harsh environment of the gastrointestinal tract and inaccessible microenvironment of fibrotic lesions seem to be no longer considered a great barrier to the use of anti‐fibrotic drugs. In this review, we comprehensively summarize recent preclinical and clinical studies on intestinal and hepatic fibrosis. It is found that the targets for preclinical studies on intestinal fibrosis is varied, which could be divided into molecular, cellular, and tissues level, although little clinical trials are ongoing. Liver fibrosis clinical trials have focused on improving metabolic disorders, preventing the activation and proliferation of hepatic stellate cells, promoting the degradation of collagen, and reducing inflammation and cell death. At the preclinical stage, the therapeutic strategies have focused on drug targets and delivery systems. At last, promising remedies to the current challenges are based on multi‐modal synergistic and targeted delivery therapies through mesenchymal stem cells, nanotechnology, and gut‐liver axis providing useful insights into anti‐fibrotic strategies for clinical use.

Introduction The increase in the number of patients with uncontrolled type 2 diabetes mellitus (T2DM) is in need of effective management interventions. However, research to date has been limited to the evaluation of the outcomes of community pharmacists alone. Therefore, the aim of the study protocol is to compare the effects of clinical pharmacist-led intervention strategies for the management of T2DM in the outpatient settings.Method and analysis The study will collect and analyse data applying standard Cochrane methodological procedures. A search for eligible studies and ongoing trials will be conducted using PubMed, Embase, Medline (via Ovid), EBSCO (via Ovid), Lippincott Williams & Wilkins (LWW) Journals (via Ovid), ProQuest Health and Medical Complete, and ClinicalTrials.gov (clinicaltrials.gov) from database inception to December 2023. Clinical and health outcomes will be measured using both glycaemic control related indicators (eg, glycated haemoglobin, fasting blood glucose, postprandial glucose) and general indicators (eg, adherence, disease management and health-related quality of life). The meta-analysis will conduct pairwise meta-analysis using random effects models and network meta-analysis (NMA) employing the Bayesian hierarchical model. The visualisation and statistical analysis will be carried out using RevMan, R Studio and ADDIS. Additionally, we will evaluate the certainty of the evidence by using Grading of Recommendations Assessment, Development and Evaluation system.Ethics and dissemination There will be no primary data collection from NMA participants, and there is no requirement for formal ethical review. Our aim is to present the results of this NMA in a peer-reviewed scientific journal, at conferences, and in the mainstream media.PROSPERO registration number CRD42022355368.

Summary: Background: Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment. Methods: This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings: Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator’s decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion. Interpretation: Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial. Funding: This study was funded by CARsgen Therapeutics Co., Ltd.

It is meaningful to find suitable in vitro models for preclinical toxicology and efficacy evaluation of nanodrugs and nanocarriers or drug screening and promoting clinical transformation of nanocarriers. The emergence and development of organoids technology provide a great possibility to achieve this goal. Herein, we constructed an in vitro 3D organoid model to study the inhibitory effect of nanocarriers on colorectal cancer. And designed hydroxyapatite nanoclusters (c-HAP) mediated by polydopamine (PDA) formed under alkaline conditions (pH 9.0), then used c-HAP to load DOX (c-HAP/DOX) as nanocarrier for improved chemotherapy. In vitro, drug release experiments show that c-HAP/DOX has suitable responsive to pH, can be triggered to the facile release of DOX in a slightly acidic environment (pH 6.0), and maintain specific stability in a neutral pH value (7.4) environment. c-HAP/DOX showed an excellent antitumor effect in the two-dimensional (2D) cell model and three-dimensional (3D) patient-derived colon cancer organoids (PDCCOs) model. In addition, c-HAP/DOX can release a sufficient amount of DOX to produce cytotoxicity in a slightly acidic environment, entering efficiently into the colorectal cancer cells caused endocytosis and induced apoptosis. Therefore, organoids can serve as an effective in vitro model to present the structure and function of colorectal cancer tissues and be used to evaluate the efficacy of nanocarriers for tumors.

BackgroundWhether irAEs can predict the efficacy of PD-1 inhibitors in cholangiocarcinoma (CCA) has not been assessed. Therefore, this study aims to investigate the correlation between irAEs and the therapeutic effect of PD-1 inhibitors combination therapy in patients with advanced CCA.MethodsAll patients with CCA who were consecutively admitted to the inpatient unit of our hospital and received PD-1 inhibitors combination therapy between September 2020 and April 2022 were screened. In total, 106 patients with CCA were screened out. We then followed up these patients until October 2022. Due to perioperative use (n=28), less than 2 cycles of PD-1 inhibitor therapy (n=9), incomplete data (n=8) and no pathological report (n=2), 59 patients were included in the final analysis. The patients were divided into the irAEs cohort and the non-irAEs cohort according to whether they experienced irAEs or not. The Log-Rank test was performed to compare the difference in survival time between these two cohorts. We then applied multivariate COX regression analysis to investigate whether irAEs were independent prognostic factors for survival in patients with advanced CCA.ResultsFinally, 32 patients were included in the irAEs cohort and 27 patients in the non-irAEs cohort. A total of 32 patients (54.2%) had any-grade irAEs, of which 4 patients (6.8%) had grade 3-4 irAEs. The most common irAEs were thyroid toxicity (30.5%) and dermatologic toxicity (30.5%). There were no notable differences in demographics and clinical characteristics between the irAEs and non-irAEs cohorts, except for total bilirubin level (P=0.026) and relapse (P=0.016). The disease control rate (DCR) in the irAEs cohort was higher than in the non-irAEs cohort (90.6% vs 70.4%, P=0.047). Median overall survival (OS) and median progression-free survival (PFS) were better in the irAEs cohort than in the non-irAEs cohort (OS: 21.2 vs 10.0 months, P

Objectives The aims of the study were to assess the management of low-density lipoprotein cholesterol (LDL-C) and the goal achievement, as well as to investigate the association between baseline LDL-C level, lipid-lowering treatment (LLT), and stroke recurrence in patients with ischaemic stroke or transient ischaemic attack (TIA).Design Our study was a post hoc analysis of the Third China National Stroke Registry (CNSR-III).Setting We derived data from the CNSR-III - a nationwide clinical registry of ischaemic stroke and TIA based on 201 participating hospitals in mainland China.Participants 15,166 patients were included in this study with demographic characteristics, etiology, imaging, and biological markers from August 2015 to March 2018.Primary and secondary outcome measures The primary outcome was a new stroke, LDL-C goal (LDL-C

Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20–24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43–118.53%, 109.13–141.88%, 109.53–139.54%, and 105.17–145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80–93.57%, 88.17–110.55, 95.72%–118.50%, and 79.77–105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

The regulation of PD-L1 via proteasomal degradation is unclear. Here, the authors show that EGFR inhibition activates GSK3 α to promote PD-L1 phosphorylation, which leads to PD-L1 ubiquitination and proteasome mediated degradation by ARIH1 E3 ligase.

ObjectiveStudies have shown a correlation between gut microbiota and anxiety and depression levels. However, these studies are mainly animal studies or clinical studies of non-cancer patients, there is still a lack of relevant studies in cancer patients. The main objective of this trial was to analyze the correlation between probiotics and anxiety and depression levels in cancer patients.MethodsWe screened all cancer patients consecutively admitted to the inpatient department of the First Affiliated Hospital, Zhejiang University School of Medicine in May 2020. A total of 292 cancer patients met our inclusion criteria. Then, we followed up all patients for 24 weeks. Patients who had incomplete data or loss of follow-up were excluded. In addition, in patients who took probiotics, those did not take probiotics consistently or did not take specific probiotics were excluded. Ultimately, the number of patients enrolled was 82 in probiotics cohort and 100 in non-probiotics cohort. The 17-item Hamilton Depression Scale (HAMD-17) questionnaire was used to measure the depression levels of the patients, and we also used Hamilton Anxiety Scale (HAMA) questionnaire to assess the patients’ anxiety levels. A logistic regression model was used to analyze whether the difference in baseline data of two cohorts would affect the final result.ResultsDemographic and clinical characteristics of all cancer patients enrolled in probiotics cohort and non-probiotics cohort were similar except the cancer therapy (P = 0.004). According to the HAMA score, we divided cancer patients into non-anxiety group (HAMA score < 14) and anxiety group (HAMA score ≥ 14). Similarly, cancer patients were also divided into non-depression group (HAMD-17 score ≤ 7) and depression group (HAMD-17 score > 7). The results demonstrated that there was no statistical difference in the proportion of patients with anxiety (6.1 and 13.0%, respectively, P = 0.121) and depression (30.5 and 23.0%, respectively, P = 0.254) between probiotics and non-probiotics cohorts. The results of logistic regression model analysis further proved that the baseline difference in cancer therapy did not affect the conclusions.ConclusionOur results still suggest that there is no significant correlation between probiotics and anxiety and depression levels in cancer patients. Therefore, we do not recommend supplementing probiotics for cancer patients to prevent anxiety and depression. Moreover, high-quality RCTs are also needed to further confirm the conclusions of this study.

Background Small single subcortical infarction (SSSI) may be classified as parent artery disease-related or only branch involved according to the stenosis of parent artery. The study aimed to evaluate short-term and long-term prognoses and the effectiveness of antiplatelet therapy in SSSI.Methods We prospectively enrolled 2890 patients with SSSI from the Third China National Stroke Registry (CNSR-III) database from August 2015 to March 2018. We assessed clinical outcomes and antiplatelet treatment effects in patients with SSSI with and without parent artery stenosis (PAS) identified by magnetic resonance angiography.Results Among 2890 patients with SSSI in the perforator territory of the middle cerebral artery and the basilar artery, there were 680 (23.53%) patients with PAS and 2210 (76.47%) patients without PAS, respectively. After adjusting for potential confounders, the PAS group had a greater initial stroke severity (OR 1.262, 95% CI 1.058 to 1.505; p=0.0097) and a higher risk of ischaemic stroke recurrence at 3 months (OR 2.266, 95% CI 1.631 to 3.149; p

Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.

Multi-scale context information, especially long-range dependency, has shown to be beneficial for speaker verification (SV) tasks. In this paper, we propose three methods to systematically explore long-range context SV feature extraction based on ResNet and analyze their complementarity. Firstly, the Hierarchical-split block (HS-block) is introduced to enlarge the receptive fields (RFs) and extract long-range context information over the feature maps of a single layer, where the multi-channel feature maps are split into multiple groups and then stacked together. Then, by analyzing the contribution of each location of the convolution kernel to SV, we find the traditional convolution with a square kernel is not effective for long-range feature extraction. Therefore, we propose cross convolution kernel (cross-conv), which replaces the original 3 × 3 convolution kernel with a 1 × 5 and 5 × 1 convolution kernel. Cross-conv further enlarges the RFs with the same FLOPs and parameters. Finally, the Depthwise Separable Self-Attention (DSSA) module uses an explicit sparse attention strategy to capture effective long-range dependencies globally in each channel. Experiments are conducted on the VoxCeleb and CnCeleb to verify the effectiveness and robustness of the proposed system. Experimental results show that the combination of HS-block, cross-conv, and DSSA module achieves better performance than any single method, which demonstrates the complementarity of these three methods.

Platinum (Pt) drugs (e.g., oxaliplatin, cisplatin) are applied in the clinic worldwide for the treatment of various cancers. However, platinum-induced peripheral neuropathy (PIPN) caused by the accumulation of Pt in the peripheral nervous system limits the clinical application, whose prevention and treatment are still a huge challenge. To date, Pt-induced reactive oxygen species (ROS) generation has been studied as one of the primary mechanisms of PIPN, whose downregulation would be feasible to relieve PIPN. This review will discuss ROS-related PIPN mechanisms including Pt accumulation in the dorsal root ganglia (DRG), ROS generation, and cellular regulation. Based on them, some antioxidant therapeutic drugs will be summarized in detail to alleviate the Pt-induced ROS overproduction. More importantly, we focus on the cutting-edge nanotechnology in view of ROS-related PIPN mechanisms and will discuss the rational fabrication of tailor-made nanosystems for efficiently preventing and treating PIPN. Last, the future prospects and potential breakthroughs of these anti-ROS agents and nanosystems will be briefly discussed.

Coronavirus disease 2019 (COVID-19) has become a global public health concern. We aimed to study the cytokine profile during the convalescent phase and its association with liver functions. We performed a retrospective study to investigate the longitudinal dynamic serum cytokine, liver function, and metabolomic profiles, as well as their potential correlations, from the viral replication phase to early convalescence. Our results demonstrated that liver injury was common. Liver injury was significantly associated with higher levels of interleukin (IL)-6 and IL-10 (p < 0.05). However, alanine aminotransferase levels decreased during the first week after hospital discharge (p < 0.01). In parallel, T-cell and B-cell immune response-stimulating cytokine IL-4, but not IL-2, was significantly elevated (p < 0.05). Furthermore, interferon-γ (IFN-γ) and tumor necrosis factor-α (TFN-α) levels increased, in contrast to the decrease in IL-6 and IL-10 levels; liver function returned to normal. The metabolomic analysis supported active recovery during early convalescence of COVID-19 patients that had distinct metabolic profiles associated with the hepatic tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. In addition, we identified a metabolomic association of IL-4 with liver repair. Our findings suggest that discharged patients continue to recover from the physiological effects of COVID-19, and the association of IL-4, IL-6, and IL-10 levels with metabolic changes and liver function repair may have important implications for clinical manifestations and treatment of COVID-19.

Abstract Background Cardiovascular events (CVEs) was considered as one of the primary cause to reduce the quality of life in breast cancer patients with aromatase inhibitors (AIs) treatment, which has not been sufficiently addressed. The aim of this study was to assess the correlation between risk of CVEs and AIs in patients with breast cancer. Methods Included studies were obtained from the databases of Embase, Pubmed, Cochrane Library, Clinical Trials.gov, and reference lists. The main outcome measures were overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Furthermore, the association and the risk differences among different tumor types, AIs,ages,or treatment regimens were conducted. Fixed-effect or random-effect models were applied in the statistical analyses according to the heterogeneity. Our analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results Seventeen studies, which included 44,411 subjects, were included in our analyses. The overall incidence of CVEs in AIs group was 13.02% (95% CI: 8.15–20.17%) and almost all of the high-grade CVEs occurred in patients treated with AIs. The pooled ORs of CVEs was 0.9940 (95% CI: 0.8545–1.1562). Under sub-group analysis, the incidence of CVEs related to exemestane was higher than that of controls (OR = 1.1564, 95% CI: 1.0656–1.2549), but no statistical differences in risk of CVEs were found in other sub-group analysis. No evidence of publication bias was found for incidence of CVEs in our meta-analysis by a funnel plot. Conclusions These results suggest that patients with breast cancer treated with AIs do not have a significant risk of developing CVEs in comparison with the controls, and exemestane might not be considered as the alternative AI to the breast cancer patients from the perspective of CVEs. Further studies are recommended to investigate this association and the risk differences among different tumor types, AIs or treatment regimens.

A simple, rapid, and sensitive liquid chromatography (LC)/mass spectrometry (MS) method was established and validated for simultaneous quantitation of pyrazinamide, isoniazid, rifampicin, and ethambutol in human blood sample. Samples were pretreated by a single-step precipitation with acetonitrile. Chromatographic separation was achieved on XSelecT HSS T3 column by gradient elution with a total run time of 5.0 min. MS detection was performed by a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode with a positive electrospray ionization source. Isotope-labeled internal standard, especially rifampicin-D8, was applied to adjust for the loss during sample treatment. The established LC-MS/MS method showed a wide analytical range (pyrazinamide: 1.02∼60.0 μg/mL, isoniazid: 0.152∼10.0 μg/mL, rifampicin: 0.500∼30.0 μg/mL, and ethambutol: 0.0998∼5.99 μg/mL) and a good linearity (r > 0.99 for the four analytes) with acceptable accuracy and precision (90.15%∼104.62% and 94.00%∼104.02% for intra- and interaccuracy, respectively; RSD%:

Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.

Objective(s): Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea) was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

Background Complementopathy (rapid complement activation and consumption after trauma) has been reported in trauma patients, but the underlying mechanism of these phenomena and their clinical significance remain unclear. This study aimed to determine the complement/complement pathway activation and identify the association of complement activation with clinical outcomes in trauma patients.Methods We studied 33 trauma patients with mean Injury Severity Score of 25, and 25 healthy volunteers. Sera were collected on patients’ arrival at the emergency department, as well as 1, 2, 3, 5, and 7 days after trauma, to measure the levels of terminal complement activation product soluble C5b-9 (sC5b-9) by ELISA. In addition, the functional complement activation pathway was evaluated using a commercial complement system screening kit.Results Serum concentrations of sC5b-9 (complement terminal pathway activity) were significantly increased in trauma patients throughout the entire observation period except on day 1. Complement terminal activities were significantly higher in 27 of 33 patients with systemic inflammatory response syndrome (SIRS) than non-SIRS patients on day 2, day 5, and day 7. Increased serum levels of sC5b-9 positively correlated with SIRS. Functional complement analysis revealed that the classical pathway was the predominant pathway responsible for complement activation. Burn patients tended to have a greater and prolonged classical pathway activation than non-burn patients, and burn injury and blunt injury were associated with higher blood levels of sC5b-9 than penetrating injury.Discussion Early complement activation through the classical pathway after trauma is observed and positively correlated with the development of SIRS. Thus, monitoring of the complement system might be beneficial in the care of critically injured patients.Level of evidence III.Study type Prognostic.