Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in gastrointestinal cancers.

Gastrointestinal (GI) cancer is a prevalent disease and is recognized as the primary cause of cancer-related mortality globally. Therefore, there is an urgent need for novel diagnostic and treatment approaches for GC. The methylation of the O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter is a significant factor in the development of colorectal cancer (CRC), namely in roughly 30-40% of cases where the cancer has spread. MGMT plays a role in the repair of DNA damage caused by methylating drugs like temozolomide (TMZ) and chloroethylating compounds like carmustine. As a result, it contributes to the resistance of chemotherapy when these agents are utilized. Although MGMT's role in the development of CRC is well established, its prognostic significance remains a subject of debate. Only a limited number of research have been conducted to examine the prognostic significance of MGMT methylation, yielding varying outcomes. This review explores the structural functions and repair processes of MGMT, focusing on the putative structural and functional significance of the N-terminal domain of MGMT. It also investigates the advancement of cancer treatment techniques that specifically target MGMT.

A multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma.

Accurate intraoperative differentiation of primary central nervous system lymphoma (PCNSL) remains pivotal in guiding neurosurgical decisions. However, distinguishing PCNSL from other lesions, notably glioma, through frozen sections challenges pathologists. Here we sought to develop and validate a deep learning model capable of precisely distinguishing PCNSL from non-PCNSL lesions, especially glioma, using hematoxylin and eosin (H&E)-stained frozen whole-slide images. Also, we compared its performance against pathologists of varying expertise. Additionally, a human-machine fusion approach integrated both model and pathologic diagnostics. In external cohorts, LGNet achieved AUROCs of 0.965 and 0.972 in distinguishing PCNSL from glioma and AUROCs of 0.981 and 0.993 in differentiating PCNSL from non-PCNSL lesions. Outperforming several pathologists, LGNet significantly improved diagnostic performance, further augmented to some extent by fusion approach. LGNet's proficiency in frozen section analysis and its synergy with pathologists indicate its valuable role in intraoperative diagnosis, particularly in discriminating PCNSL from glioma, alongside other lesions.

Structure and activity of the septal peptidoglycan hydrolysis machinery crucial for bacterial cell division.

The peptidoglycan (PG) layer is a critical component of the bacterial cell wall and serves as an important target for antibiotics in both gram-negative and gram-positive bacteria. The hydrolysis of septal PG (sPG) is a crucial step of bacterial cell division, facilitated by FtsEX through an amidase activation system. In this study, we present the cryo-EM structures of Escherichia coli FtsEX and FtsEX-EnvC in the ATP-bound state at resolutions of 3.05 Å and 3.11 Å, respectively. Our PG degradation assays in E. coli reveal that the ATP-bound conformation of FtsEX activates sPG hydrolysis of EnvC-AmiB, whereas EnvC-AmiB alone exhibits autoinhibition. Structural analyses indicate that ATP binding induces conformational changes in FtsEX-EnvC, leading to significant differences from the apo state. Furthermore, PG degradation assays of AmiB mutants confirm that the regulation of AmiB by FtsEX-EnvC is achieved through the interaction between EnvC-AmiB. These findings not only provide structural insight into the mechanism of sPG hydrolysis and bacterial cell division, but also have implications for the development of novel therapeutics targeting drug-resistant bacteria.

Enhancement of doxorubicin production in Streptomyces peucetius by genetic engineering and process optimization.

Doxorubicin is an important class of anthracycline antitumor antibiotics produced by Streptomyces peucetius. The doxorubicin fermentation yield of the wild-type strain was very low, so it could not be produced directly by fermentation at an industrial scale due to the high cost. In the present study, S. peucetius SIPI-7-14 was obtained from SIPI-14 through several rounds of doxorubicin resistance screening. Then, the ketoreductase gene dnrU was knocked out to reduce (13S)-13-dihydrodaunorubicin production, and the resistance gene drrC was overexpressed to further enhance resistance to doxorubicin. The resulting engineered strain S. peucetius △U1/drrC produced 1128 mg/L doxorubicin, a 102.1% increase compared to that of SIPI-14. Then, fermentation medium was optimized using the response surface method. In the optimized fermentation medium, the yield of doxorubicin was increased to 1406 mg/L in shake flask on the 7th day. Furthermore, batch culture was carried out in a 10 L fermenter, and the concentration of doxorubicin reached 1461 mg/L after 7 days of culture, which was the highest yield reported to date, indicating the potential for industrial production of doxorubicin by fermentation.

Selective microRNA expression of exosomes from retinal pigment epithelial cells by oxidative stress.

The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1ß, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future.

Angiogenic and Fibrogenic Dual-effect of Gremlin1 on Proliferative Diabetic Retinopathy.

Ocular angiogenic diseases, such as proliferative diabetic retinopathy (PDR), are often characterized by pathological new vessels and fibrosis formation. Anti-vascular endothelial growth factor (VEGF) therapy, despite of its efficiency to inhibit new vessels, has limitations, including drug resistance and retinal fibrosis. Here, we identified that Gremlin1, a novel angiogenesis and fibrosis inducer, was secreted from Müller glial cells, and its expression increased in the vitreous fluid from patients with PDR. Mechanistically, Gremlin1 triggered angiogenesis by promoting endothelial-mesenchymal transition via the EGFR/RhoA/ROCK pathway. In addition, Gremlin1 activated microglia to present profibrotic and fibrogenic properties. Further, anti-Gremlin1 antibody inhibited ocular angiogenesis and microglia fibrosis in mouse models. Collectively, Gremlin1 could be a potential therapeutic target in the treatment of ocular angiogenic diseases.

OHCCPredictor: an online risk stratification model for predicting survival duration of older patients with hepatocellular carcinoma.

BACKGROUND: Although the elderly constitute more than a third of hepatocellular carcinoma (HCC) patients, they have not been adequately represented in treatment and prognosis studies. Thus, there is not enough evidence to guide the treatment of such patients. The objective of this study is to identify the prognostic factors of older patients with HCC and to construct a new prognostic model for predicting their overall survival (OS). METHODS: 2,721 HCC patients aged ≥ 65 were extracted from the public database-Surveillance, Epidemiology, and End Results (SEER) and randomly divided into a training set and an internal validation set with a ratio of 7:3. 101 patients diagnosed from 2008 to 2017 in the First Affiliated Hospital of Zhejiang University School of Medicine were identified as the external validation set. Univariate cox regression analyses and multivariate cox regression analyses were adopted to identify these independent prognostic factors. A predictive nomogram-based risk stratification model was proposed and evaluated using area under the receiver operating characteristic curve (AUC), calibration curves, and a decision curve analysis (DCA). RESULTS: These attributes including age, sex, marital status, T stage, N stage, surgery, chemotherapy, tumor size, alpha-fetoprotein level, fibrosis score, bone metastasis, lung metastasis, and grade were the independent prognostic factors for older patients with HCC while predicting survival duration. We found that the nomogram provided a good assessment of OS at 1, 3, and 5 years in older patients with HCC (1-year OS: (training set: AUC = 0.823 (95%CI 0.803-0.845); internal validation set: AUC = 0.847 (95%CI 0.818-0.876); external validation set: AUC = 0.732 (95%CI 0.521-0.943)); 3-year OS: (training set: AUC = 0.813 (95%CI 0.790-0.837); internal validation set: AUC = 0.844 (95%CI 0.812-0.876); external validation set: AUC = 0.780 (95%CI 0.674-0.887)); 5-year OS: (training set: AUC = 0.839 (95%CI 0.806-0.872); internal validation set: AUC = 0.800 (95%CI 0.751-0.849); external validation set: AUC = 0.821 (95%CI 0.727-0.914)). The calibration curves showed that the nomogram was with strong calibration. The DCA indicated that the nomogram can be used as an effective tool in clinical practice. The risk stratification of all subgroups was statistically significant (p < 0.05). In the stratification analysis of surgery, larger resection (LR) achieved a better survival curve than local destruction (LD), but a worse one than segmental resection (SR) and liver transplantation (LT) (p < 0.0001). With the consideration of the friendship to clinicians, we further developed an online interface (OHCCPredictor) for such a predictive function ( https://juntaotan.shinyapps.io/dynnomapp_hcc/ ). With such an easily obtained online tool, clinicians will be provided helpful assistance in formulating personalized therapy to assess the prognosis of older patients with HCC. CONCLUSIONS: Age, sex, marital status, T stage, N stage, surgery, chemotherapy, tumor size, AFP level, fibrosis score, bone metastasis, lung metastasis, and grade were independent prognostic factors for elderly patients with HCC. The constructed nomogram model based on the above factors could accurately predict the prognosis of such patients. Besides, the developed online web interface of the predictive model provide easily obtained access for clinicians.

[Retracted] miR­141 inhibits prostatic cancer cell proliferation and migration, and induces cell apoptosis via targeting of RUNX1.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that a number of plates showing colony formation assay data in Fig. 3A appeared to be overlapping, such that data purportedly showing the results from differently performed experiments may have been derived from the same original source(s); furthermore, certain of the cell­cycle histograms shown in Fig. 4B were duplicated, again where they were intended to have shown results obtained under different experimental conditions. Subsequently, following an independent enquiry in the office, it was also noted that, in Fig. 2B, the data shown for the RUNX1 western blots were apparently the same for both the DU145 and PC­2 cell lines. Although a corrigendum was requested by the authors, given the extent of the errors that were identified with respect to the compilation of as many as three of the figures in this paper, the Editor of Oncology Reports has decided that this article should be retracted from the publication owing to a lack of overall confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience that might result from the retraction of this article. [Oncology Reports 39: 1454­1460, 2018; DOI: 10.3892/or.2018.6209].

High-titer production of staurosporine by heterologous expression and process optimization.

Staurosporine is the most well-known member of the indolocarbazole alkaloid family; it can induce apoptosis of many types of cells as a strong protein kinase inhibitor, and is used as an important lead compound for the synthesis of the antitumor drugs. However, the low fermentation level of the native producer remains the bottleneck of staurosporine production. Herein, integration of multi-copy biosynthetic gene cluster (BGC) in well characterized heterologous host and optimization of the fermentation process were performed to enable high-level production of staurosporine. First, the 22.5 kb staurosporine BGC was captured by CRISPR/Cas9-mediated TAR (transformation-associated recombination) from the native producer (145 mg/L), and then introduced into three heterologous hosts Streptomyces avermitilis (ATCC 31267), Streptomyces lividans TK24 and Streptomyces albus J1074 to evaluate the staurosporine production capacity. The highest yield was achieved in S. albus J1074 (750 mg/L), which was used for further production improvement. Next, we integrated two additional staurosporine BGCs into the chromosome of strain S-STA via two different attB sites (vwb and TG1), leading to a double increase in the production of staurosporine. And finally, optimization of fermentation process by controlling the pH and glucose feeding could improve the yield of staurosporine to 4568 mg/L, which was approximately 30-fold higher than that of the native producer. This is the highest yield ever reported, paving the way for the industrial production of staurosporine. KEYPOINTS: • Streptomyces albus J1074 was the most suitable heterologous host to express the biosynthetic gene cluster of staurosporine. • Amplification of the biosynthetic gene cluster had obvious effect on improving the production of staurosporine. • The highest yield of staurosporine was achieved to 4568 mg/L by stepwise increase strategy.

Stapedius muscle: Don't mistake it for a branch of the facial nerve in images.

OBJECTIVE: The relationship between the stapedius muscle and the vertical part of the facial nerve is important for surgery. The study aims to understand the spatial relationship between the stapedius muscle and the vertical part of the facial nerve in ultra-high-resolution computed tomography (U-HRCT) images. METHODS: A total of 105 ears from the heads of 54 human cadavers were analyzed using U-HRCT. The location and direction of the stapedius muscle were evaluated with the facial nerve as the reference. The integrity of the bony septum between the two structures and the distance between the transverse sections were examined. Paired Student's t-test and the nonparametric Wilcoxon test were applied. RESULTS: The lower end of the stapedius muscle emerged at the upper (45 ears), middle (40 ears), or lower (20 ears) level of the facial nerve and was positioned medial (32 ears), medial posterior (61 ears), posterior (11 ears), or lateral posterior (1 ear) to the facial nerve. The bony septum was not continuous in 99 ears. The distance between the midpoints of the two structures was 1.75 mm (IQR=1.55-2.16 mm). CONCLUSION: The spatial relationship between the stapedius muscle and the facial nerve was varied. They were close to each other and in most cases the bony septum was not intact. Preoperative familiarity with the relationship between the two structures is helpful for avoiding unwanted injury to the facial nerve in surgery.

An exploratory study of imaging diagnostic clues for overhanging facial nerve in ultra-high-resolution CT.

PURPOSE: Overhanging facial nerve (FN) may be challenging in imaging diagnosis. The purpose of the study is to investigate the imaging clues for overhanging FN near the oval window on ultra-high-resolution computed tomography (U-HRCT) images. METHODS: Between October 2020 and August 2021, images of 325 ears (276 patients) were included in the analysis obtained by an experimental U-HRCT scanner. On standard reformatted images, the morphology of FN was evaluated and its position was quantitatively measured using the following indices: protrusion ratio (PR), protruding angle (A), position of FN (P-FN), distance between FN and stapes (D-S), and distance between FN and anterior and posterior crura of stapes (D-AC and D-PC). According to the FN morphology in imaging, images were divided into overhanging FN group and non-overhanging FN group. Binary univariate logistic regression analysis was used to identify the imaging indices independently associated with overhanging FN. RESULTS: Overhanging FN was found in 66 ears (20.3%), which manifested as downwards protrusion of either local segment (61 ears, 61/66) or the entire course near the oval window (5 ears, 5/66). D-AC [odds ratio: 0.063, 95% CI 0.012-0.334, P = 0.001) and D-PC (odds ratio: 0.008, 95% CI 0.001-0.050, P = 0.000) were identified as independent predictors of FN overhang (area under the curve: 0.828 and 0.865, respectively). CONCLUSION: Abnormal morphology of the lower margin of FN, D-AC and D-PC on U-HRCT images provide valuable diagnostic clues for FN overhang.

A novel model for predicting prolonged stay of patients with type-2 diabetes mellitus: a 13-year (2010-2022) multicenter retrospective case-control study.

BACKGROUND: Length of stay (LOS) is an important metric for evaluating the management of inpatients. This study aimed to explore the factors impacting the LOS of inpatients with type-2 diabetes mellitus (T2DM) and develop a predictive model for the early identification of inpatients with prolonged LOS. METHODS: A 13-year multicenter retrospective study was conducted on 83,776 patients with T2DM to develop and validate a clinical predictive tool for prolonged LOS. Least absolute shrinkage and selection operator regression model and multivariable logistic regression analysis were adopted to build the risk model for prolonged LOS, and a nomogram was taken to visualize the model. Furthermore, receiver operating characteristic curves, calibration curves, and decision curve analysis and clinical impact curves were used to respectively validate the discrimination, calibration, and clinical applicability of the model. RESULTS: The result showed that age, cerebral infarction, antihypertensive drug use, antiplatelet and anticoagulant use, past surgical history, past medical history, smoking, drinking, and neutrophil percentage-to-albumin ratio were closely related to the prolonged LOS. Area under the curve values of the nomogram in the training, internal validation, external validation set 1, and external validation set 2 were 0.803 (95% CI [confidence interval] 0.799-0.808), 0.794 (95% CI 0.788-0.800), 0.754 (95% CI 0.739-0.770), and 0.743 (95% CI 0.722-0.763), respectively. The calibration curves indicated that the nomogram had a strong calibration. Besides, decision curve analysis, and clinical impact curves exhibited that the nomogram had favorable clinical practical value. Besides, an online interface ( https://cytjt007.shinyapps.io/prolonged_los/ ) was developed to provide convenient access for users. CONCLUSION: In sum, the proposed model could predict the possible prolonged LOS of inpatients with T2DM and help the clinicians to improve efficiency in bed management.

A novel imaging scoring method for identifying facial canal dehiscence: an ultra-high-resolution CT study.

OBJECTIVES: Facial canal dehiscence (FCD), typically found in the tympanic segment, is a risk factor for facial nerve injury. An imaging scoring method was proposed to identify FCD based on ultra-high-resolution CT. METHODS: Forty patients (21 females and 19 males, mean age 44.3 ± 17.4 years), whose tympanic facial canal (FC) was examined during otological surgery, were divided into the FCD group (n = 29) and the control group (n = 11) based on surgical findings. Imaging appearance of tympanic FC was scored 0-3: 0 = no evident bony covering, 1 = discontinuous bony covering with linear deficiency, 2 = discontinuous bony covering with dotted deficiency, and 3 = continuous bony covering. Both lateral and inferior walls were assigned a score as LFCD and IFCD, respectively. An FCD score was calculated as LFCD + IFCD. The diagnostic value of the FCD score was tested using the ROC curve. RESULTS: The inter-observer agreement was moderate for the lateral wall (Cohen's κ coefficient 0.416, 95% CI 0.193-0.639), and good for the inferior wall (Cohen's κ coefficient 0.702, 95% CI 0.516-0.888). In the FCD group, the most common appearance for both walls was discontinuous bony covering with linear deficiency (LFCD = 1, 22/29, 75.9%; IFCD = 1, 15/29, 51.7%). An FCD score of less than 4 was associated with high sensitivity (0.82) and specificity (0.93) for identifying FCD, with an AUC of 0.928. CONCLUSIONS: Using the proposed scoring method, FCD score < 4 could identify FCD of the tympanic segment with high concordance with surgical findings. KEY POINTS: • Imaging appearance of the tympanic facial canal (FC) is divided into four types based on ultra-high-resolution CT images. • The most common appearance of FC with facial canal dehiscence (FCD) is discontinuous bony covering with linear deficiency. • An FCD score, consisting of scores of the lateral and inferior walls, less than 4 is highly indicative of FCD.

Interleukin-1 receptor-associated kinase 2 promotes inflammatory reactions by activating the nuclear factor kappa-B signaling pathway in diabetic nephropathy.

Diabetic nephropathy (DN) is a major complication of diabetes. Interleukin-1 receptor-associated kinase 2 (IRAK2) has been implicated in various diseases. This study aimed to investigate the role of IRAK2 in DN progression and its association with inflammation and the nuclear factor-kappa B (NF-κB) signaling pathway. DN model mice were generated by intraperitoneal injection of streptozotocin. IRAK2 expression was upregulated in the DN model mice. IRAK2 knockdown increased weight and reduced blood glucose levels in DN model mice. In addition, IRAK2 downregulation improved glomerular morphology in DN mice. IRAK2 knockdown reduced the levels of kidney damage biomarkers (24-h urinary protein, urine albumin-creatinine ratio, and plasma creatinine) and inflammatory cytokines (IL-6, tumor necrosis factor [TNF]-α, TNF-1R, and TNF-2R). Moreover, IRAK2 activated the NF-κB signaling pathway in DN model mice. Overexpression of NF-κB exacerbated DN progression, and IRAK2 knockdown reversed these effects. IRAK2 promoted DN progression and inflammation by activating the NF-κB signaling pathway. These findings suggest that IRAK2 is a potential therapeutic target for DN treatment.

Delayed pain relief in patients with trigeminal neuralgia following microvascular decompression: A single-central retrospective study.

Background: Compared to hemifacial spasm after microvascular decompression (MVD), delayed relief (DR) rarely occurs in patients with trigeminal neuralgia (TGN). Objective: To analyze the characteristics of post-MVD DR in TGN patients to provide useful clues for the clinical differential diagnosis of postoperative DR. Methods: The clinical data of all patients with TGN who underwent MVD in our center from January 1, 2016, to December 31, 2020, were reviewed retrospectively. Results: In 272 TGN MVD patients, DR occurred in nine patients (3.3%) during the follow-up periods of 1-6 years. During surgery, all nine DR-TGN patients were identified as having neurovascular conflicts (NVCs), involving the offending artery (OA) in eight patients (two OAs in two patients) and both an artery and a vein in the other patient. The compression site was near the root entry zone (REZ) in most DR patients (7/9). Delayed relief was relieved in seven patients within 5 days after surgery and within 30 days in the other two patients. No recurrence or serious complications were observed within the mean 4 (1-6)-year follow-up duration. Conclusion: Delayed relief rarely occurs in TGN patients after MVD. Neurovascular conflicts located at the REZ and NVC of grade III may be two important factors contributing to DR in TGN patients. Delayed relief may occur when the pain gradually improves after the operation and responds effectively to a small dose of carbamazepine. The recurrence rate of TGN seems even lower in such patients.

Advances in the application of proteomics in lung cancer.

Although the incidence and mortality of lung cancer have decreased significantly in the past decade, it is still one of the leading causes of death, which greatly impairs people's life and health. Proteomics is an emerging technology that involves the application of techniques for identifying and quantifying the overall proteins in cells, tissues and organisms, and can be combined with genomics, transcriptomics to form a multi-omics research model. By comparing the content of proteins between normal and tumor tissues, proteomics can be applied to different clinical aspects like diagnosis, treatment, and prognosis, especially the exploration of disease biomarkers and therapeutic targets. The applications of proteomics have promoted the research on lung cancer. To figure out potential applications of proteomics associated with lung cancer, we summarized the role of proteomics in studies about tumorigenesis, diagnosis, prognosis, treatment and resistance of lung cancer in this review, which will provide guidance for more rational application of proteomics and potential therapeutic strategies of lung cancer.

Radiological Evaluation of Tympanic Segment of Chorda Tympani Nerve in Normal Ears: An Ultra-High-Resolution Computed Tomography Study.

BACKGROUND: To visualize the course of the tympanic segment of chorda tympani nerve (CTN) using ultra-high-resolution computed tomography. METHODS: A hundred and fourteen ears with no evident otologic pathologies were included. The tympanic segment of CTN was divided into 4 portions as follows: periannular, posteromalleal, malleal, and anteromalleal. The length of the periannular portion running along the tympanic annulus was recorded. Four points of interest (the beginning and end of the posteromalleal and anteromalleal portions) were selected to perform distance measurements relative to the tip of the malleus manubrium. Differences in lengths and distances were compared in terms of ear sides and sexes. RESULTS: The length of the periannular portion was 2.49 ± 1.16 mm. The beginning of the posteromalleal portion was located more laterally on the right side than on the left side (mean: 4.09 mm vs. 3.92 mm;, P = 0.016). The end of the posteromalleal portion was located more inferiorly on the right (mean: 2.11 mm vs. 2.26 mm; P = 0.018). The beginning of the anteromalleal portion on the right was located more laterally than that on the left (mean: 2.60 mm vs. 2.45 mm; P = 0.027). The start and end of the anteromalleal portion were more posteriorly located in women than in men (both Ps < 0.001). CONCLUSIONS: The course of the tympanic segment of normal CTN was comprehensively visualized by ultra-high-resolution computed tomography. Preoperative evaluation of the tympanic segment of CTN might be helpful in avoiding iatrogenic injury during middle ear surgery.

Comprehensive Evaluation of Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 and Their Combined Immunotherapy in Clinical Trials: A Systematic Review and Meta-analysis.

Immunotherapy with immune checkpoint inhibitor (ICI) drugs is gradually becoming a hot topic in cancer treatment. To comprehensively evaluate the safety and efficacy of ICI drugs, we employed the Bayesian model and conducted a network meta-analysis in terms of progression-free survival (PFS), overall survival (OS) and severe adverse events (AEs). Our study found that treatment with ipilimumab was significantly worse than standard therapies in terms of PFS, whereas treatment with cemiplimab significantly improved PFS. The results also indicated that cemiplimab was the best choice for PFS. Treatment with nivolumab, pembrolizumab and nivolumab plus ipilimumab significantly improved OS compared to standard therapies. In terms of OS, cemiplimab was found to be the best choice, whereas avelumab was the worst. In terms of severe AEs, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab all significantly reduced the risk of grade 3 or higher AEs compared to standard therapy. The least likely to be associated with severe AEs were as follows: cemiplimab, avelumab, nivolumab, atezolizumab, and camrelizumab, with nivolumab plus ipilimumab to be the worst. Therefore, different ICI drug therapies may pose different risks in terms of PFS, OS and severe AEs. Our study may provide new insights and strategies for the clinical practice of ICI drugs.

Evidence for adduction of biologic amines with reactive metabolite of 8-epidiosbulbin E acetate in vitro and in vivo.

Dioscorea bulbifera L. (DBL) is one of traditional Chinese medicines and has been used for the treatment of goiter, tumor and carbuncles. However, clinic application of the herbal medicine has been limited, due to reported severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the major components of DBL, can cause severe liver damage. The furan ring of EEA is metabolized by CYP3A4 to a cis-enedial reactive intermediate prone to react amino and/or thiol groups of amino acid residues. In this study, we investigated the interaction of the reactive intermediate with biologic amines. EEA-derived biologic amine adducts, including spermidine, spermine, putrescine, ornithine, lysine and glutamine were detected in cultured mouse primary hepatocytes treated with EEA. Only spermidine adduct was observed in bile of mice given EEA. The detection of the adducts was established by labeling with bromobenzyl mercaptan and LC-MS/MS analysis. Exposure of EEA resulted in concentration dependent cytotoxicity in hepatocytes. Pretreatment with spermidine attenuated the susceptibility of cells to the cytotoxicity of EEA, because of the compensation of the depleted spermidine.

Vitreous Inflammatory Cytokines and Chemokines, Not Altered After Preoperative Adjunctive Conbercept Injection, but Associated With Early Postoperative Macular Edema in Patients With Proliferative Diabetic Retinopathy.

Purpose: To investigate the influence of preoperative adjunctive anti-VEGF drug (Conbercept) on vitreous inflammatory cytokines and chemokines profiles and whether those cytokines were associated with early macular edema (ME) after surgery for patients with proliferative diabetic retinopathy (PDR). Methods: In this post hoc analysis of the CONCEPT clinical trial, subjects with PDR underwent vitrectomy were included and vitreous samples were collected at the start of vitrectomy. Levels of vitreous VEGF, 17 inflammatory cytokines, and 11 chemokines were measured using Luminex multiplex technology. Subjects were then divided into groups based on with (Pre-IV) or without (No-Pre-IV) preoperative intravitreous injection of Conbercept; with or without early ME after surgery. Results: There was no difference between Pre-IV (13/30) and No-Pre-IV (7/29) concerning the ratio of patients with early ME (p = 0.17). After preoperative intravitreous injection of Conbercept, VEGF level dramatically decreased (p = 0.001), TNF-α (p = 0.002), and IP-10 (p = 0.018) increased in Pre-IV group. In patients with early ME after surgery, however, a number of cytokines increased, including IL-1ß (p = 0.008), IL-2 (p = 0.023), IL-4 (p = 0.030), IL-9 (p = 0.02), IL-10 (p = 0.002), IL-12 (p = 0.001), IL-13 (p = 0.031), IL-17A (p = 0.008), TNF-α (p = 0.012), CXCL9 (p = 0.023), G-CSF (p = 0.019), MCP-1 (p = 0.048), and RANTES (p = 0.016). Conclusion: We found the preoperative adjunctive Conbercept injection has limited influence on the levels of vitreous inflammatory cytokines and chemokines in PDR. The elevated levels of a series of cytokines might be associated with early inflammation after vitrectomy, which may lead to postoperative ME.