[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

The postoperative analgesic efficacy of different regional anesthesia techniques in breast cancer surgery: A network meta-analysis.

Background: Regional anesthesia have been successfully performed for pain management in breast cancer surgery, but it is unclear which is the best regional anesthesia technique. The aim of the present network meta-analysis was to assess the analgesic efficacy and disadvantages of regional anesthesia techniques. Methods: Multiple databases were searched for randomized controlled trials (RCTs). The association between regional anesthesia and analgesic efficacy was evaluated by Bayesian network meta-analysis. Results: We included 100 RCTs and 6639 patients in this study. The network meta-analysis showed that paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion were associated with significantly decreased postoperative pain scores, morphine consumption and incidence of postoperative nausea and vomiting compared with no block. Regarding the incidence of chronic pain, no significance was detected between the different regional anesthesia techniques. In the cumulative ranking curve analysis, the rank of the rhomboid intercostal block was the for postoperative care unit pain scores, postoperative 24-hour morphine consumption, and incidence of postoperative nausea and vomiting. Conclusion: Regional anesthesia techniques including, paravertebral nerve block, pectoral nerve-2 block, serratus anterior plane block, erector spinae plane block, rhomboid intercostal block, and local anesthetic infusion, can effectively alleviate postoperative acute analgesia and reduce postoperative morphine consumption, but cannot reduce chronic pain after breast surgery. The rhomboid intercostal block might be the optimal technique for postoperative analgesia in breast cancer surgery, but the strength of the evidence was very low. Systematic review registration: https://www.crd.york.ac.uk/prospero/(PROSPERO), identifier CRD 42020220763.

The safety of perioperative dexamethasone with antiemetic dosage in surgical patients with diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Dexamethasone is commonly used for antiemesis in surgical patients. It has been confirmed that long-term steroid use increases blood glucose level in both diabetic and non-diabetic patients, it is unclear how a single dose of intravenous dexamethasone used pre/intraoperatively for postoperative nausea and vomiting (PONV) prophylaxis would influence the blood glucose and wound healing in diabetic patients. METHODS: The Pubmed, Cochrane Library, Embase, Web of Science databases, CNKI and Google Scholar were searched. The articles reporting a single dose dexamethasone administered intravenously for antiemesis in surgical patients with diabetes mellitus (DM) were included. RESULTS: Nine randomized controlled trials (RCTs) and 7 cohort studies were included in our meta-analysis. The results showed that dexamethasone increased glucose level intraoperatively (MD: 0.439, 95% CI: 0.137-0.581, I2 = 55.7%, P = 0.004), at the end of surgery (MD: 0.815, 95% CI: 0.563-1.067, I2 = 73.5%, P = 0.000), on postoperative day (POD) 1 (MD: 1.087, 95% CI: 0.534-1.640, I2 = 88%, P = 0.000), on POD 2 (MD: 0.501, 95% CI: 0.301-0.701, I2 = 0%, P = 0.000), and increased peak glucose level within 24 hours of surgery (MD: 2.014, 95% CI: 0.503-3.525, I2 = 91.6%, P = 0.009) compared with control. It indicated that dexamethasone caused the increase of perioperative glucose level at different time points by 0.439 to 1.087 mmol/L (7.902 to 19.566 mg/dL), and the increase of peak glucose level within 24 hours of surgery by 2.014 mmol/L (36.252 mg/dL) compared with control. Dexmethasone had no impact on wound infection (OR: 0.797, 95%CI: 0.578-1.099, I2 = 0%, P = 0.166) and healing (P < 0.05). CONCLUSION: Dexamethasone could increase blood glucose by only 2.014 mmol/L (36.252 mg/dL) of peak glucose level within 24 hours of surgery in surgery patients with DM, the increase of glucose level at each time point perioperatively was even lower, and had no effect on wound healing. Thus, dexamethasone with a single dose could be safely used for PONV prophylaxis in diabetic patients. TRIAL REGISTRATION: The protocol of this systematic review was registered in INPLASY with the registration number INPLASY202270002.

Potent Anti-SARS-CoV-2 Efficacy of COVID-19 Hyperimmune Globulin from Vaccine-Immunized Plasma.

Coronavirus disease 2019 (COVID-19) remains a global public health threat. Hence, more effective and specific antivirals are urgently needed. Here, COVID-19 hyperimmune globulin (COVID-HIG), a passive immunotherapy, is prepared from the plasma of healthy donors vaccinated with BBIBP-CorV (Sinopharm COVID-19 vaccine). COVID-HIG shows high-affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, the receptor-binding domain (RBD), the N-terminal domain of the S protein, and the nucleocapsid protein; and blocks RBD binding to human angiotensin-converting enzyme 2 (hACE2). Pseudotyped and authentic virus-based assays show that COVID-HIG displays broad-spectrum neutralization effects on a wide variety of SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) in vitro. However, a significant reduction in the neutralization titer is detected against Beta, Delta, and Omicron variants. Additionally, assessments of the prophylactic and treatment efficacy of COVID-HIG in an Adv5-hACE2-transduced IFNAR-/- mouse model of SARS-CoV-2 infection show significantly reduced weight loss, lung viral loads, and lung pathological injury. Moreover, COVID-HIG exhibits neutralization potency similar to that of anti-SARS-CoV-2 hyperimmune globulin from pooled convalescent plasma. Overall, the results demonstrate the potential of COVID-HIG against SARS-CoV-2 infection and provide reference for subsequent clinical trials.

Agent Clustering Strategy Based on Metabolic Flux Distribution and Transcriptome Expression for Novel Drug Development.

The network module-based method has been used for drug repositioning. The traditional drug repositioning method only uses the gene characteristics of the drug but ignores the drug-triggered metabolic changes. The metabolic network systematically characterizes the connection between genes, proteins, and metabolic reactions. The differential metabolic flux distribution, as drug metabolism characteristics, was employed to cluster the agents with similar MoAs (mechanism of action). In this study, agents with the same pharmacology were clustered into one group, and a total of 1309 agents from the CMap database were clustered into 98 groups based on differential metabolic flux distribution. Transcription factor (TF) enrichment analysis revealed the agents in the same group (such as group 7 and group 26) were confirmed to have similar MoAs. Through this agent clustering strategy, the candidate drugs which can inhibit (Japanese encephalitis virus) JEV infection were identified. This study provides new insights into drug repositioning and their MoAs.

Development of specific and selective bactericide by introducing exogenous metabolite of pathogenic bacteria.

The widespread and repeated use of broad-spectrum bactericides has led to an increase in resistance. Developing novel broad-spectrum bactericides cannot solve the resistance problem, and may even aggravate it. The design of specific and selective bactericides has become urgent. A specific bactericidal design strategy was proposed by introducing exogenous metabolites in this study. This strategy was used to optimize two known antibacterial agents, luteolin (M) and Isoprothiolane (D), against Xoo. Based on the prodrug principles, target compound MB and DB were synthesized by combing M or D with exogenous metabolites, respectively. Bactericidal activity test results demonstrated that while the antibacterial ability of target compounds was significantly improved, their selectivity was also well enhanced by the introducing of exogenous metabolites. Comparing with the original compound, the antibacterial activity of target compound was significantly increased 92.0% and 74.5%, respectively. The optimized target compounds were more easily absorbed, and the drug application concentrations were much lower than those of the original agents, which would greatly reduce environmental pollution and relieve resistance risk. Our proposed strategy is of great significance for exploring the specific and selective bactericides against other pathogens.

The Analgesic Effects of Thoracic Paravertebral Block versus Thoracic Epidural Anesthesia After Thoracoscopic Surgery: A Meta-Analysis.

BACKGROUND: To date, there is no definitive evidence for the analgesic effects and side effects of thoracic epidural anesthesia (TEA) versus thoracic paravertebral block (TPVB) after thoracoscopic surgery. In this study, we conducted a meta-analysis of published randomized clinical trials (RCTs) to analyze the analgesic effects of TEA versus TPVB after thoracoscopic surgery. METHODS: We systematically searched RCTs published by October 26, 2020, in PubMed, EMBASE, and Cochrane library and conducted a meta-analysis to analyze the analgesic effects of TEA versus TPVB after thoracoscopic surgery. The primary measure was postoperative pain score, and the secondary measures were postoperative 24-hour usage of opioids, hypotension, postoperative nausea, and vomiting. RESULTS: A total of 458 patients from five RCTs were included in this study. After thoracoscopic surgery, the numerical rating scale (NRS) score for resting pain was higher in the TPVB group than in the TEA group at 1-2 hours and 4-6 hours after surgery (MD = 0.44, 95% CI = 0.24 to 0.64, P < 0.0001, I2 = 0%; MD = 0.47, 95% CI = 0.23 to 0.70, P < 0.0001, I2 = 0%). The postoperative 24-hour usage of morphine was higher in the TPVB group than in the TEA group (SMD = 0.67; 95% CI = 0.03 to 1.31; P = 0.04; I2 = 84%). The incidence of hypotension was significantly lower in the TPVB group than in the TEA group (OR = 4.52; 95% CI = 2.03 to 10.10; P = 0.0002; I2 = 0%). No significant between-group difference was observed in postoperative nausea and vomiting (PONV). CONCLUSION: Compared with TPVB, TEA provides statistically significant but clinically unimportant short-term benefits following thoracoscopic surgery.

An analysis of the mechanism underlying photocatalytic disinfection based on integrated metabolic networks and transcriptional data.

Photocatalytic disinfection has long been used to combat pathogenic bacteria. However, the specific mechanism underlying photocatalytic disinfection and its corresponding targets remain unclear. In this study, an analysis of the potential mechanism underlying photocatalytic disinfection was performed based on integrated metabolic networks and transcriptional data. Two sets of RNA-seq data (wild type and a photocatalysis-resistant mutant mediated by titanium dioxide (TiO2)) were processed to constrain the genome scale metabolic models (GSMM) of E. coli. By analyzing the metabolic network, the differential metabolic flux of every reaction was computed in constrained GSMM, and several significantly differential metabolic fluxes in reactions were extracted and analyzed. Most of these reactions were involved in the transmembrane transport of substances and occurred on the inner membrane or were an important component of the cell membrane. These results, which are consistent with the reported information, validated our analysis process. In addition, our work also identified other new and valuable metabolic pathways, such as the reaction ALCD2x, which has a great effect on the energy production process under bacterial anaerobic conditions. The DHAK reaction is also related to the metabolic process of ATP. These reactions with large differential metabolic fluxes merit further research. Additionally, to provide a strategy to address photocatalysis-resistant mutant bacteria, a metabolic compensation analysis was also performed. The metabolic compensation analysis results provided suggestions for a combined method that can effectively combat resistant bacteria. This method could also be used to explore the mechanisms of drug resistance in other microorganisms.

Functional characterization of 27 CYP3A4 variants on macitentan metabolism in vitro.

OBJECTIVE: Macitentan is a new choice for pulmonary hypertension treatment which is converted to active metabolite ACT132577 by human cytochrome P450 3A4. Human cytochrome P450 3A4 often occurred gene mutations. Gene polymorphism might cause a variety of changes of protein expression and thus give rise to metabolic difference. The aim of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the metabolism of macitentan in vitro. METHOD: The incubation mixtures (final volume of 200 µl in 1 m PBS) consisted of 1 pmol wild-type CYP3A4.1 or other CYP3A4 protein variants, 2.38 pmol CYP b5 and macitentan (10-600 µm) with 1 mm NADPH. All specimens were processed using same approach with acetonitrile precipitation. The metabolite of macitentan was analysed by ultra performance liquid chromatography-tandem mass spectrometry. KEY FINDING: Most CYP3A4 protein variants (CYP3A4.9, .11, .12, .13, .17, .20, .23, .24, .28, .29, .33, .34) exhibited a sharp decrease, meanwhile nearly one in five variants (CYP3A4.3, .4, .5, .10, .15, .16) showed a significant rise in intrinsic clearance. The relative clearance of CYP3A4 protein variants was ranged from 5.53 to 501.00%. CONCLUSION: Twenty-seven CYP3A4 protein variants displayed different catalytic characteristics towards macitentan in vitro, especially CYP3A4.5, .17, .20, .23. It is important to pay more attention to the dosage of macitentan in order to get better treatment for pulmonary arterial hypertension.

PSME3 Promotes TGFB1 Secretion by Pancreatic Cancer Cells to Induce Pancreatic Stellate Cell Proliferation.

Pancreatic cancer is a highly malignant disease that is associated with poor prognosis. One hallmark of pancreatic cancer is excessive desmoplasia, characterized by fibrous or connective tissue growth and altered tumor stroma. Pancreatic stellate cells (PSCs) comprise a mesenchymal cell type that contributes to pancreas fibrosis and cancer progression. PSME3 is a regulatory subunit of the proteasome that is expressed in various cancers such as breast, ovarian, and pancreatic. Notably, PSME3 modulates lactate secretion in pancreatic cancer, suggesting a potential function in regulating pancreas fibrosis. However, the role of PSME3 in pancreatic cancer cell (PCC)-PSC interactions remains unclear. The current study, for the first time, explored the mechanism involved in PSME3-mediated PCC-PSC interactions. IHC showed that PSME3 is highly expressed in PCCs, and this was found to correlate with tumor differentiation. RNA interference (RNAi) indicated that PSME3 is involved in PCC apoptosis. PCR array and cell co-culture experiments suggested that conditioned culture medium (CM) from PSME3-knockdown PCCs could suppress PSC proliferation by down-regulating TGFB1 secretion. Transcription factor (TF) activation assays showed that PSME3 regulates TGFB1 production by inhibiting activation protein-1 (AP-1). Together, these data demonstrate that PSME3 interacts with AP-1 to regulate TGFB1 secretion in PCCs and promote PSC proliferation. Our results indicate a novel PSME3-regulated association between PSCs and PCCs and provide a promising therapeutic strategy for this malignancy.

Differences between low and high grade fetal adenocarcinoma of the lung: a clinicopathological and molecular study.

BACKGROUND: Fetal adenocarcinoma of the lung (FLAC) is a rare entity of lung cancer. It is classified into low-grade fetal adenocarcinoma (L-FLAC) and high-grade fetal adenocarcinoma (H-FLAC). We aim to report the clinicopathological and molecular features of FLAC in Chinese patients. METHODS: FLACs were screened from a consecutive lung adenocarcinoma series comprising 920 cases. The clinicopathological features L-FLAC and H-FLAC were retrospectively reviewed via immunohistochemical study and mutation analysis. RESULTS: Three L-FLAC and five H-FLAC cases were identified. L-FLAC mainly occurred in young patients and was predominantly in stage I upon diagnosis and conferred favorable outcomes. L-FLAC tumors were characterized by the glycogen-rich columnar cells lining the complex glandular structures, with low nuclear atypia, morule formation, and mainly nuclear- and cytoplasmic-localized ß-catenin expression. In contrast, H-FLAC predominantly occurred in elderly men with a history of smoking. The stage of H-FLAC was often advanced at presentation and had a poor prognosis. H-FLAC tumors exhibited more prominent atypia of the nucleus, the absence of morule formation, and largely membrane-localized ß-catenin. All 5 H-FLACs were immunohistochemically characterized by overexpression of the p53 protein; the L-FLAC tumors were negative for p53. Two cases of H-FLAC were positive for AFP. No Her-2 or ALK-D5F3 overexpression was observed in any of the tumors. EGFR L858R point mutation was identified in one of the H-FLAC cases. EGFR T790M mutation was detected in one of the L-FLAC cases. No mutations in KRAS, PIK3CA or BRAF were detected. CONCLUSIONS: L-FLAC and H-FLAC exhibited distinctive clinicopathological, immunophenotypic and molecular features with potential prognostic value.

Near-infrared dye-loaded magnetic nanoparticles as photoacoustic contrast agent for enhanced tumor imaging.

Objective: Photoacoustic (PA) tomography (PAT) has attracted extensive interest because of its optical absorption contrast and ultrasonic detection. This study aims to develop a biocompatible and biodegradable PA contrast agent particularly promising for clinical applications in human body. Methods: In this study, we presented a PA contrast agent: 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy (polyethylene glycol)] (DSPE-PEG)-coated superparamagnetic iron oxide (SPIO) nanoparticles (NPs) loaded with indocyanine green (ICG). We used ICG and SPIO NPs because both drugs are approved by the U.S. Food and Drug Administration. Given the strong absorption of near-infrared laser pulses, SPIO@DSPE-PEG/ICG NPs with a uniform diameter of ~28 nm could significantly enhance PA signals. Results: We demonstrated the contrast enhancement of these NPs in phantom and animal experiments, in which the in vivo circulation time of SPIO@DSPE-PEG/ICG NPs was considerably longer than that of free ICG. These novel NPs also displayed a high efficiency of tumor targeting. Conclusions: SPIO@DSPE-PEG/ICG NPs are promising PAT contrast agents for clinical applications.

[Construction and evaluation of an engineered bacterial strain for producing lipopeptide under anoxic conditions].

Biosurfactant-facilitated oil recovery is one of the most important aspects of microbial enhanced oil recovery (MEOR). However, the biosurfactant production by biosurfactant-producing microorganisms, most of which are aerobes, is severely suppressed due to the in-situ anoxic conditions within oil reservoirs. In this research, we successfully engineered a strain JD-3, which could grow rapidly and produce lipopeptide under anoxic conditions, by protoplast confusion using a Bacillus amyloliquefaciens strain BQ-2 which produces biosurfactant aerobically, and a facultative anaerobic Pseudomonas stutzeri strain DQ-1 as parent strains. The alignment of 16S rDNA sequence (99% similarity) and comparisons of cell colony morphology showed that fusant JD-3 was closer to the parental strain B. amyloliquefaciens BQ-2. The surface tension of culture broth of fusant JD-3, after 36-hour cultivation under anaerobic conditions, decreased from initially 63.0 to 32.5 mN · m(-1). The results of thin layer chromatography and infrared spectrum analysis demonstrated that the biosurfactant produced by JD-3 was lipopeptide. The surface-active lipopeptide had a low critical micelle concentration (CMC) of 90 mg · L(-1) and presented a good ability to emulsify various hydrocarbons such as crude oil, liquid paraffin, and kerosene. Strain JD-3 could utilize peptone as nitrogen source and sucrose, glucose, glycerin or other common organics as carbon sources for anaerobic lipopeptide synthesis. The subculture of fusant JD-3 showed a stable lipopeptide-producing ability even after ten serial passages. All these results indicated that fusant JD-3 holds a great potential to microbially enhance oil recovery under anoxic conditions.

Chitosan stabilized Prussian blue nanoparticles for photothermally enhanced gene delivery.

The lack of biosafety and insufficient delivery efficiency of gene-carriers are still obstacles to human gene therapy. This paper reported highly biocompatible chitosan (CS) functionalized Prussian blue (PB) nanoparticles (designated as CS/PB NPs) for photocontrollable gene delivery. The ultra-small size (∼3 nm), positive charge and high physiological stability of CS/PB NPs make it suitable to be a nonviral vector. In addition, CS/PB NPs could effectively convert the near infrared (NIR) light into heat due to its strong absorption in the NIR region, assisting the uptake of NPs by cells. Upon NIR light irradiation, CS/PB NPs showed superior gene transfection efficiency, much higher than that of free polyethylenimine (PEI). Both in vitro and in vivo experiments demonstrated that CS/PB NPs had excellent biocompatiblity. This work also encourages further exploration of the CS/PB NPs as a photocontrollable nanovector for combined photothermal and gene therapy.

Imaging guided photothermal therapy using iron oxide loaded poly(lactic acid) microcapsules coated with graphene oxide.

A novel multifunctional theranostic agent has been successfully fabricated by loading iron oxide nanoparticles into poly(lactic acid) (PLA) microcapsules followed by surface functionalization with graphene oxide. Both in vitro and in vivo experiments proved that the resulting microcapsules could serve as contrast agents to simultaneously enhance ultrasound, magnetic resonance and photoacoustic imaging. The composite microcapsules show good biocompatibility and rapid response to magnetic fields. Due to the strong absorption of the near-infrared light, the composite microcapsules could efficiently kill cancer cells upon NIR laser irradiation. In addition, it was found that such a photothermal effect could be obviously enhanced by applying an external magnetic field. In a nutshell, this multifunctional microcapsule can be developed as a promising platform that integrates multimodality imaging and therapy capabilities for effective cancer theranostics.

[Self-made ultrasound/fluorescent bi-functional contrast agent for rabbit's normal lymph node imaging].

OBJECTIVE: To prepare a lymph node-targeted ultrasound/fluorescence bi-functional imaging contrast agents, and observe its effectiveness both on contrast-enhanced ultrasound (CEUS) and vivo near infrared fluorescence (NIR) imaging through animal experiments. METHODS: The chimeric lymph node-targeted ligand (phosphatidylserine) and near-infrared fluorescent substance were assembled to form bi-functional contrast microbubbles. The morphology and size distribution were detected by optical microscope and Malvern potential tests. Five normal New Zealand white rabbits were subcutaneously injected with the prepared contrast agent in bilateral footpads, and the imaging effectiveness of lymph nodes and lymphatic vessel were observed by CEUS and NIR technique. Then blue dye was subcutaneously injected at the same site, and the rabbits were sacrificed for lymph nodes pathological examination. RESULTS: Lipid ultrasound microbubbles,with a mean size of 3-5 Μm in diameter, appeared to be uniform in distribution and regular in configuration. The images of inflow lymphatic vessel and relevant lymph node were quickly showed up after the subcutaneous injection by CEUS, which was identical to the result detected by NIR. Biopsy confirmed that all the blue-stained lymph nodes could be displayed by NIR. CONCLUSIONS: The self-made bi-functional contrast agent has a good imaging ability in CEUS and NIR imaging. It may be a better agent as lymph node tracer.