Outcome of Transcatheter Aortic Valve Replacement for Pure Native Aortic Regurgitation in Patients with Pulmonary Hypertension.

Background: In recent years, transcatheter aortic valve replacement (TAVR) has emerged as a pivotal treatment for pure native aortic regurgitation (PNAR). Given patients with severe aortic regurgitation (AR) are prone to suffer from pulmonary hypertension (PH), understanding TAVR's efficacy in this context is crucial. This study aims to explore the short-term prognosis of TAVR in PNAR patients with concurrent PH. Methods: Patients with PNAR undergoing TAVR at Zhongshan Hospital, Affiliated with Fudan University, were enrolled between June 2018 to June 2023. They were categorized based on pulmonary artery systolic pressure (PASP) into groups with or without PH. The baseline characteristics, imaging records, and follow-up data were collected. Results: Among the 103 patients recruited, 48 were afflicted with PH. In comparison to PNAR patients without PH, the PH group exhibited higher rates of renal dysfunction (10.4% vs. 0.0%, p = 0.014), increased Society of Thoracic Surgeons scores (6.4 ± 1.9 vs. 4.7 ± 1.6, p < 0.001), and elevated Nterminal fragment of pro-brain natriuretic peptide (NT-proBNP). Transthoracic ultrasound examination revealed that patients with PH displayed lower left ventricular ejection fraction, larger left ventricle dimension, and more frequent moderate to severe tcuspid regurgitation (TR). Following TAVR, both groups experienced significant reductions in PASP, mitral regurgitation (MR) and TR. There were no significant differences in the incidence of postoperative adverse events in patients with or without PH. Conclusions: We found TAVR to be a safe and effective treatment for patients with PNAR and PH, reducing the degree of aortic regurgitation and PH without increasing the risk of postoperative adverse events.

The changing scenario of drug discovery using AI to deep learning: Recent advancement, success stories, collaborations, and challenges.

Due to the transformation of artificial intelligence (AI) tools and technologies, AI-driven drug discovery has come to the forefront. It reduces the time and expenditure. Due to these advantages, pharmaceutical industries are concentrating on AI-driven drug discovery. Several drug molecules have been discovered using AI-based techniques and tools, and several newly AI-discovered drug molecules have already entered clinical trials. In this review, we first present the data and their resources in the pharmaceutical sector for AI-driven drug discovery and illustrated some significant algorithms or techniques used for AI and ML which are used in this field. We gave an overview of the deep neural network (NN) models and compared them with artificial NNs. Then, we illustrate the recent advancement of the landscape of drug discovery using AI to deep learning, such as the identification of drug targets, prediction of their structure, estimation of drug-target interaction, estimation of drug-target binding affinity, design of de novo drug, prediction of drug toxicity, estimation of absorption, distribution, metabolism, excretion, toxicity; and estimation of drug-drug interaction. Moreover, we highlighted the success stories of AI-driven drug discovery and discussed several collaboration and the challenges in this area. The discussions in the article will enrich the pharmaceutical industry.

The Antiphytopathogenic Metabolites and the Synergy of Endophytes Paraphaeosphaeria sp., Nigrospora oryzae from the Same Ginkgo biloba Host.

Two endophytes from the same Ginkgo biloba host were isolated and cultured separately. Three new eremophilane sesquiterpenoids (1-3), three new furan derivates (6, 8-9), one new polyketide (10), and four known compounds (4, 5, 7, 11) from Paraphaeosphaeria sp. and two new 10-membered macrolides (12-13), a new liner polyketide (14), a new benzofuran (15), and six known compounds (16-21) from Nigrospora oryzae were isolated. The structures of the isolated compounds were determined by spectroscopic methods, NMR calculations, and ECD calculations. The compounds 3-7, 9-10, 12, and 14-17 showed significant antiphytopathogenic effects against mycotoxigenic Alternaria sp. comparable to the activity of nystatin (positive control). Compounds 2, 6, 8, 9, and 18 indicated inhibitions against phytopathogen Fusarium asiaticum with MICs < 10 µg/mL. In addition, the compounds with weak antifungal activities from two endophytes were mixed to test their antifungal activity. The results showed that the metabolites from two endophytes had synergistic antifungal effects, and the beneficial interactions between natural products can induce more antifungal effects against plant pathogens than that of single compounds.

Perioperative, functional, and oncologic outcomes in obese patients undergoing Da Vinci robot-assisted radical prostatectomy: a systematic review and meta-analysis.

OBJECTIVE: The influence of robot-assisted radical prostatectomy (RARP) in obese (OB) and non-obese (NOB) prostate cancer patients remains a topic of debate. The objective of this study was to juxtapose the perioperative, functional, and oncologic outcomes of RARP in OB and NOB cohorts. MATERIALS AND METHODS: We systematically searched the databases such as PubMed, Embase, Web of Science, and the Cochrane Library database to identify relevant studies published in English up to September 2023. Review Manager was used to compare various parameters. The study was registered with PROSPERO (CRD42023473136). Sixteen comparative trials were included for 8434 obese patients compared with 55,266 non-obese patients. RESULTS: The OB group had a longer operative time (WMD 17.8 min, 95% CI 9.7,25.8; p < 0.0001), a longer length of hospital stay (WMD 0.18 day, 95% CI 0.12,0.24; p < 0.00001, a higher estimated blood loss (WMD 50.6 ml, 95% CI 11.7,89.6; p = 0.01), and higher pelvic lymphadenectomy rate (RR 1.08, 95% CI 1.04,1.12; p < 0.0001)and lower nerve sparing rate (RR 0.95, 95% CI 0.91,0.99; p < 0.01), but there was no difference between unilateral (RR 1.0, 95% CI 0.8,1.3; p = 0.8)and bilateral (RR 0.9, 95% CI 0.9,1.0; p = 0.06)nerve sparing rate. Then, complication rates (RR 1.6, 95% CI 1.5,1.7; p < 0.00001) were higher in the OB group, and both major (RR 1.4, 95% CI 1.1,1.8; p = 0.01)and minor (RR 1.4, 95% CI 1.1,1.7; p < 0.01)complication rates were higher in the OB group. Moreover, obese patients showed significantly higher probabilities of incontinence (RR 1.17, 95% CI 1.03,1.33; p = 0.01) and impotency (RR 1.08, 95% CI 1.01,1.15; p = 0.02) at 1 year. Last, the positive surgical margin (RR 1.2, 95% CI 1.1,1.3; p < 0.01) was higher in the OB group. CONCLUSION: In the obese group, perioperative outcomes, total complications, functional outcomes, and oncologic outcomes were all worse for RARP. Weight loss before RARP may be a feasible strategy to improve the prognosis of patients.

Association Between Systemic Inflammation Response Index and Slow Coronary Flow Phenomenon in Patients with Ischemia and No Obstructive Coronary Arteries.

Background: Inflammation plays a key role in the pathogenesis of slow coronary flow phenomenon (SCFP). SCFP is a condition that can complicate the management of ischemia and no obstructive coronary arteries (INOCA), making it essential to identify reliable predictors. Although the systemic inflammation response index (SIRI) has been proven to relate to various cardiovascular diseases. However, the predictive value of SIRI for SCFP in patients with INOCA remains unclear. Methods: A total of 1422 patients with INOCA were consecutively included in this study. 89 individuals were diagnosed with SCFP (the SCFP group). A 1:2 age- and -sex-matched patients with INOCA and normal blood flow were selected as the control group (n=178). Plasma neutrophil, monocyte, and lymphocyte counts were collected so as to determine the value of SIRI. Results: Patients with SCFP had an elevated level of body mass index (BMI) and an increased incidence of smoking and diabetes. The SIRI was significantly higher in the SCFP group than in the controls (2.3±1.3 vs 1.8±1.3, p=0.002). The SIRI increased as the number of coronary arteries involved in the SCFP increased. Univariate analyses showed that BMI, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and SIRI were associated with SCFP. Multivariate logistic regression analysis revealed that BMI and SIRI were independent predictors of SCFP occurrence. The ROC curve showed that when the SIRI was > 1.140, the sensitivity and specificity were 87.6% and 60.1%, respectively, and the area under the ROC curve (AUC) was 0.644 (95% CI: 0.578-0.710, P < 0.001). Conclusion: The findings demonstrated that an increased SIRI may have a potential role in distinguishing SCFP in patients with INOCA. SIRI could improve the predictive value of SCFP compared to neutrophils, monocytes, and lymphocytes alone.

Ecosystem regime shifts and its application prospects to ecosystem management in cold and arid regions.

Ecosystem regime shifts refer to the drastically changes of an ecosystem from one state to another after suffering disturbances that exceed the thresholds. Although land desertification and grassland degradation, which are common in the cold and arid regions, are gradual processes, sudden changes can also occur when the duration or intensity of disturbances exceed the thresholds. Therefore, the study of ecosystem regime shifts is of great significance to the management of ecosystems in cold and arid regions. In this review, we summarized the evolution of ecosystem regime shift theory and early warning signals, and analyzed the problems of land desertification and grassland degradation in cold and arid regions, as well as potential responses of ecosystems to different stresses. We further put forward research frameworks for the evolution and mutation characteristics of the rain-fed artificial sand fixation system and alpine meadows. The future research needed to be strengthened in identifying the key drivers of ecosystem regime shifts at different stages, determining the corresponding thresholds, emphasizing the mechanism of water-limited mutation induced by extreme climatic events and its early warning, and promoting the application of regime shift research to ecosystem management in arid and arid regions.

Soft Corals-derived Dihydrosinularin Attenuates Neuronal Apoptosis in 6-hydroxydopamine-induced Cell Model of Parkinson's Disease by Regulating the PI3K Pathway.

BACKGROUND: Parkinson's disease (PD) is an irreversible, progressive disorder that profoundly impacts both motor and non-motor functions, thereby significantly diminishing the individual's quality of life. Dihydrosinularin (DHS), a natural bioactive molecule derived from soft corals, exhibits low cytotoxicity and anti-inflammatory properties. However, the therapeutic effects of DHS on neurotoxins and PD are currently unknown. OBJECTIVE: This study investigated whether DHS could mitigate 6-hydroxydopamine (6- OHDA)-induced neurotoxicity and explored the role of neuroprotective PI3K downstream signaling pathways, including that of AKT, ERK, JNK, BCL2, and NFκB, in DHS- mediated neuroprotection. METHOD: We treated the human neuroblastoma cell line, SH-SY5Y, with the neurotoxin 6-OHDA to establish a cellular model of PD. Meanwhile, we assessed the anti-apoptotic and neuroprotective properties of DHS through cell viability, apoptosis, and immunostaining assays. Furthermore, we utilized the PI3K inhibitor LY294002 to validate the therapeutic target of DHS. RESULTS: Based on the physicochemical properties of DHS, it can be inferred that it has promising oral bioavailability and permeability across the blood-brain barrier (BBB). It was demonstrated that DHS upregulates phosphorylated AKT and ERK while downregulating phosphorylated JNK. Consequently, this enhances the expression of BCL2, which exerts a protective effect on neuronal cells by inhibiting caspase activity and preventing cell apoptosis. The inhibition of PI3K significantly reduced the relative protective activity of DHS in 6-OHDA-induced neurotoxicity, suggesting that the neuroprotective effects of DHS are mediated through the activation of PI3K signaling. CONCLUSION: By investigating the mechanisms involved in 6-OHDA-induced neurotoxicity, we provided evidence concerning the therapeutic potential of DHS in neuroprotection. Further research into DHS and its mechanisms of action holds promise for developing novel therapeutic strategies for PD.

Characterization and identification of the wide-polarity multicomponents from Prunella vulgaris by offline two-dimensional liquid chromatography and hydrophilic interaction chromatography coupled to ion mobility-quadrupole time-of-flight mass spectrometry.

Metabolites identification is crucial to develop functional foods or perform quality control. Prunella vulgaris (Xia-Ku-Cao) is a medicinal and edible plant used as the herbal medicine or main additive in functional beverage. However, current analytical strategies can only on-line characterize tens of compounds, restricted by insufficient chromatographic resolution and low coverage of the mass spectrometric scan methods. This work was designed to characterize the wide-polarity components from the ear of P. vulgaris. The total extract was fractionated by semi-preparative high-performance liquid chromatography into the retained medium-polarity fraction and unretained polar fraction, which were further analyzed by offline two-dimensional liquid chromatography (2D-LC) and hydrophilic interaction chromatography, respectively. Data-independent high-definition MSE of the Vion™ ion mobility time-of-flight mass spectrometer was utilized enabling the high-coverage acquisition of collision-induced dissociation-MS2 data. The offline 2D-LC, configuring the XBridge Amide and HSS T3 columns, gave high orthogonality (0.81) and effective peak capacity (1555). Automatic peak annotation facilitated by the UNIFI™ bioinformatics platform and comparison with 62 reference compounds achieved the efficient and more reliable structural elucidation. We could characterize 255 compounds from P. vulgaris, with numerous phenylpropanoid phenolic acids and triterpenoid O-glycosides newly reported. Especially, collision cross section (CCS) prediction and targeted isolation of three compounds assisted in the identification of 39 groups of isomers. Additionally, 17 hydrophilic compounds, involving oligosaccharides and organic acids, were characterized from the unretained polar fraction. Conclusively, the in-depth metabolites identification of P. vulgaris was accomplished, and the results can benefit the development and better quality control of this valuable plant.

Air-ventilated normothermic mechanical perfusion improves susceptibility to donation after circulatory death and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis.

End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.

Rational Design of a Multi-epitope Vaccine Using Neoantigen Against Colorectal Cancer Through Structural Immunoinformatics and ML-Enabled Simulation Approach.

Colorectal cancer poses a substantial global health burden. Regarding WHO, the global burden of colorectal cancer will be about 3.2 million new cases by the year 2040. Simultaneously, it indicated that this cancer will cause 6 million deaths per year. Despite advancements in chemotherapy and monoclonal antibody therapy, the disease remains a significant challenge due to the resistance of cancer stem cells. This study endeavors to design a multi-epitopic peptide (9-mer epitopes) neoantigen-based vaccine targeting the TLR4/MD2 complex as a potential vaccine candidate. These tumor-specific neoantigens (TSA) are considered novel antigens that can be used for vaccine development against cancer. To develop the neoantigen vaccine candidate, we used the SPENCER database, and 140 lncRNA-derived epitopes were retrieved. From 140 epitopes, we selected seven neoantigens with high antigenic properties for the vaccine construct. A novel vaccine containing epitopes, linkers (EAAAK and CPCPG), and adjuvants (ribosomal [50S] protein L7L12) was formulated utilizing immunoinformatics tools. The vaccine's biophysical properties were evaluated, revealing its antigenicity (0.6469), stability (instability index: 37.05), and potential for immune system interaction. In-depth structural analyses, molecular docking studies, and ML-enabled immune simulation profiling underscored the vaccine's structural integrity, binding affinity with TLR4, and ability to elicit robust immune responses against colorectal cancer antigens. These findings suggest that the multi-epitopic vaccine holds promise as a next-generation approach to combat colorectal cancer. Our in silico studies exhibit potentiality of the vaccine candidate; however, further in vivo and in vitro investigations are crucial to validate immunogenicity, safety, and efficacy before clinical implementation. Our study developed a first-time lncRNA-derived neoantigen-based cancer vaccine.

A Prediction Model for Detecting Dysthyroid Optic Neuropathy Based on Clinical Factors and Imaging Markers of the Optic Nerve and Cerebrospinal Fluid in the Optic Nerve Sheath.

OBJECTIVE: This study aimed to develop and test a model for predicting dysthyroid optic neuropathy (DON) based on clinical factors and imaging markers of the optic nerve and cerebrospinal fluid (CSF) in the optic nerve sheath. METHODS: This retrospective study included patients with thyroid-associated ophthalmopathy (TAO) without DON and patients with TAO accompanied by DON at our hospital. The imaging markers of the optic nerve and CSF in the optic nerve sheath were measured on the water-fat images of each patient and, together with clinical factors, were screened by Least absolute shrinkage and selection operator. Subsequently, we constructed a prediction model using multivariate logistic regression. The accuracy of the model was verified using receiver operating characteristic curve analysis. RESULTS: In total, 80 orbits from 44 DON patients and 90 orbits from 45 TAO patients were included in our study. Two variables (optic nerve subarachnoid space and the volume of the CSF in the optic nerve sheath) were found to be independent predictive factors and were included in the prediction model. In the development cohort, the mean area under the curve (AUC) was 0.994, with a sensitivity of 0.944, specificity of 0.967, and accuracy of 0.901. Moreover, in the validation cohort, the AUC was 0.960, the sensitivity was 0.889, the specificity was 0.893, and the accuracy was 0.890. CONCLUSIONS: A combined model was developed using imaging data of the optic nerve and CSF in the optic nerve sheath, serving as a noninvasive potential tool to predict DON.

Comparing the effect of FUAS and myomectomy on the elasticity of myometrium around targeted uterine fibroid.

BACKGROUND: Focused ultrasound ablation surgery (FUAS) has been widely employed to treat patients with uterine fibroid (UF). This study aimed to estimate myometrial stiffness changes in patients who received FUAS for UFs or myomectomy (ME) and compare the recovery of surrounding myometrium between FUAS and ME groups. Our results may provide more evidence for guiding the proper conception timing in patients with UF. METHODS: This study enrolled 173 patients from May 2022 to August 2023. Shear wave elastography (SWE) was used to dynamically monitor myometrial elasticity changes in patients before and after surgery. Moreover, our study monitored and analyzed the stiffness changes in the targeted fibroid after FUAS, as well as in the myometrium around after FUAS or ME. RESULTS: The stiffness of the myometrium around the resected fibroid was significantly higher than at the preoperative level until 6 months. Conversely, the stiffness of the surrounding myometrium was only temporarily increased 1 day after FUAS. The comparison between FUAS and ME groups regarding the stiffness of the surrounding myometrium showed that nonsignificant differences were detected between the two groups before the treatment. The stiffness of the surrounding myometrium in the ME group was statistically significantly higher than that of the FUAS group 1 day as well as 1, 3, and 6 months after the treatment, respectively. CONCLUSION: The FUAS had less impact on the surrounding myometrium than the ME, which may be more conducive to the recovery of myometrial elasticity in patients with UF.

Anti-photoaging activity of triterpenoids isolated from Centella asiatica.

Centella asiatica (L.) Urban is a medical plant rich in triterpenoids, frequently used in Asia to treat skin conditions such as acne. To search for anti-photoaging agents, 16 known triterpenoids and five undescribed triterpenoids, including three ursane, one oleanane and one nor-ursane were isolated from the whole herb of C. asiatica. The structures and relative stereochemistry of these compounds were elucidated by detailed NMR spectra and HRESIMS. Compounds 1 and 2 were isomers of ursane-type and oleane-type triterpenes with rare aldehyde groups on C-23. Compound 4 was a unique example of a nor-ursane type triterpenoid. The Ultraviolet B (UVB) induced HaCaT cell damage model was used to measure the in vitro anti-photoaging activity of all 21 compounds. Twenty compounds significantly increased HaCaT viability and inhibited lactate dehydrogenase (LDH) release after UVB exposure. These findings highlight the protective effects of C. asiatica-derived triterpenoids against UVB damage and indicate their potential as natural agents that can protect the skin against photoaging.

A systematic review and meta-analysis compared the safety and effectiveness of the AirSeal system with traditional pneumoperitoneum systems in robot-assisted laparoscopic urologic surgery.

This study aimed to analyze perioperative results in robot-assisted laparoscopic urological surgeries, comparing the AirSeal system with traditional pneumoperitoneum systems. This study adhered to the PRISMA guidelines for conducting systematic reviews and meta-analyses. Extensive searches were conducted in PubMed, EMBASE, and Google Scholar, including randomized controlled trials (RCTs) and cohort studies up to June 15, 2024. A combined examination of the studies found that the AirSeal system had superior results in terms of surgery duration, end-tidal carbon dioxide levels, and tidal volume compared to the traditional pneumoperitoneum system. During robotic-assisted partial nephrectomy, the AirSeal team experienced a notable decrease in surgical time, ETCO2, and VT. In addition, the occurrence of SCE was lower in the AirSeal group. However, there were no significant differences observed between the groups regarding EBL, LOHS, overall complications, and major complications. Compared to conventional pneumoperitoneum systems, the AirSeal system offers several advantages in robot-assisted laparoscopic urological surgery: reduced operative time, lower end-tidal CO2 pressure, and decreased tidal volume. Furthermore, implementing the AirSeal system does not lead to higher rates of complications, estimated blood loss, or lengthier hospital stays.

Cord blood vitamin A and vitamin D levels in relation to physical growth in exclusively breastfed infants aged 0-6 months.

Background: Vitamins A and D are essential for the health of pregnant women and infants. Nevertheless, the relationship between umbilical cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants remains uncertain. Objective: This cohort study aims to examine the relationship between cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants aged 0-6 months. Methods: 140 singleton mother-infant pairs were recruited in total. Questionnaires were used to collect maternal and infant information, and liquid chromatography was utilized to quantify the levels of vitamins A and D in the umbilical cord blood. Anthropometric measurements were conducted at birth, at 3 and 6 months of age, and the weight-for-age z-score (WAZ), length-for-age z-score (LAZ), head circumference-for-age z-score (HAZ), and BMI-for-age z-score (BMIZ) were calculated. Univariate and multivariate linear regression models were used for the analysis. Results: The average concentration of vitamins A and D in cord blood was 0.58 ± 0.20 µmol/L and 34.07 ± 13.35 nmol/L, both below the normal range for children. After adjusting for confounding factors, vitamin A levels in cord blood positively correlated with HAZ growth in infants aged 3-6 months (ß= 0.75, P < 0.01) while vitamin D levels negatively correlated with LAZ growth (ß= -0.01, P = 0.01) and positively correlated with BMIZ growth (ß= 0.02, P < 0.01). Conclusion: Higher Vitamin A levels at birth promote HAZ growth in infants aged 3-6 months while higher vitamin D levels at birth promote BMIZ growth in infants aged 3-6 months. Clinical trial registration: https://register.clinicaltrials.gov, identifier NCT04017286.

The anti-angiogenic and anti-vasculogenic mimicry effects of GN25 in endothelial and glioma cells.

BACKGROUND AND PURPOSE: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM. EXPERIMENTAL APPROACH: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways. KEY RESULTS: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures. CONCLUSION AND IMPLICATIONS: This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.

Assessing Functional Recovery of Eupneic Diaphragm Activity Following Unilateral Cervical Spinal Cord Injury in Rats.

Following cSCI, activation of the DIAm can be impacted depending on the extent of the injury. The present manuscript describes a unilateral C2 hemisection (C2SH) model of cSCI that disrupts eupneic ipsilateral diaphragm (iDIAm) electromyographic (EMG) activity during breathing in rats. To evaluate recovery of DIAm motor control, the extent of deficit due to C2SH must first be clearly established. By verifying a complete initial loss of iDIAm EMG during breathing, subsequent recovery can be classified as either absent or present, and the extent of recovery can be estimated using the EMG amplitude. Additionally, by measuring the continued absence of iDIAm EMG activity during breathing after the acute spinal shock period following C2SH, the success of the initial C2SH may be validated. Measuring contralateral diaphragm (cDIAm) EMG activity can provide information about the compensatory effects of C2SH, which also reflects neuroplasticity. Moreover, DIAm EMG recordings from awake animals can provide vital physiological information about the motor control of the DIAm after C2SH. This article describes a method for a rigorous, reproducible, and reliable C2SH model of cSCI in rats, which is an excellent platform for studying respiratory neuroplasticity, compensatory cDIAm activity, and therapeutic strategies and pharmaceuticals.

The role of adjuvant chemotherapy after radical surgery in patients with lymph node-positive bladder cancer or locally advanced (pT3, pT4a) bladder cancer: A meta-analysis and systematic review.

PURPOSE: This study aims to evaluate the impact of adjuvant chemotherapy (AC) on survival outcomes in patients with lymph node-positive bladder cancer or locally advanced (pT3, pT4a) bladder cancer after surgery. We also seek to identify which patients with pN+ bladder cancer are most likely to benefit from AC after radical cystectomy (RC). METHODS: We searched databases including Embase, PubMed, Cochrane, and ClinicalTrials.gov to identify relevant literature published in English up to February 2024. We used Stata to compare various parameters. The study has been registered in PROSPERO. RESULTS: A total of 21 studies were analyzed, including 1 randomized controlled trial, 6 prospective studies, and 14 retrospective studies, encompassing 12,888 patients. The meta-analysis showed that for patients with lymph node-positive bladder cancer, the adjuvant chemotherapy (AC) group had higher overall survival (OS) (I2=58.2%, HR 0.69; 95% CI: 0.57-0.83; P=0.019) and recurrence-free survival (RFS) (I2=66.6%, HR 0.71; 95% CI: 0.57-0.89; P=0.006) compared to the radical cystectomy (RC) group. For patients with pT3 and pT4a bladder cancer, the AC group had higher overall survival (OS) (I2=57.3%, HR 0.77; 95% CI: 0.67-0.89; P=0.022) and cancer-specific survival (CSS) (I2=47.2%, HR 0.75; 95% CI: 0.64-0.88; P=0.0048) compared to the RC group. At the same time, according to the different chemotherapy regimens, we divided the cisplatin-based chemotherapy regimen and carboplatin based chemotherapy or other regimens into two subgroups for analysis, and found that the OS (I2=41.4%, HR 0.64; 95%CI: 0.51~0.80; P=0.000) was better than carboplatin and other chemotherapy regimens (I2=64.1%, HR 0.77; 95%CI: 069~0.86; P=0.000); Lymph node density (LND) was found to be an independent predictor of overall survival (HR=1.6; 95% CI: 1.31-1.95; P=0.0000). CONCLUSION: This study found that postoperative adjuvant chemotherapy (AC) improves overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) in patients with pT3, pT4a, It was also confirmed that cisplatin-based chemotherapy regimen was more beneficial for patients with bladder cancer; and lymph node-positive bladder cancer. Additionally, our analysis revealed that patients with lymph node-positive bladder cancer benefit more from postoperative AC. It was further demonstrated that cisplatin-based chemotherapy regimens are more beneficial than other regimens for patients with locally advanced bladder cancer.

Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

Efficacy and safety of platelet-rich plasma (PRP) in erectile dysfunction (ED): a systematic review and meta-analysis.

Background: Erectile dysfunction (ED) is a prevalent condition in aging men. Meanwhile, platelet-rich plasma (PRP), an emerging treatment alternative, has demonstrated potential in mitigating symptoms associated with ED. Our research aimed to explore the safety and effectiveness of employing PRP as a treatment strategy for ED. Methods: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols, our research involved a thorough search across multiple databases: PubMed, Web of Science, Embase, and the Cochrane Controlled Trials Register. To assess the methodological rigor of the studies selected, we applied the modified Jadad scale and the Methodological Index for Non-Randomized Studies (MINORS) scale as evaluation tools. Subsequent to these evaluations, data analysis was conducted. Results: Our analysis included seven non-randomized studies and three randomized controlled trials (RCTs). These studies showed that the International Index of Erectile Function-Erectile Function (IIEF-EF) scores improved significantly after 1, 3, and 6 months of PRP treatment, with increases of 4.05 [95% confidence interval (CI): 2.42, 5.68; P<0.001], 3.73 (95% CI: 2.93, 4.53; P<0.001), and 3.92 (95% CI: 3.00, 4.85; P<0.001) respectively, compared to the baseline scores. Additionally, compared to the placebo group, the PRP group showed significantly higher IIEF-EF scores. PRP treatment also had a beneficial impact on minimal clinically important difference (MCID) and peak systolic velocity (PSV). However, no significant differences were found between the PRP and placebo groups in terms of erectile hardness score (EHS) [mean difference (MD) =0.63; 95% CI: 0.26, 0.99; P<0.001] or visual analog scale (VAS) pain scores (MD =0.24; 95% CI: -0.05, 0.54; P=0.11). Conclusions: Our study results demonstrated significant efficacy and safety of PRP in treating ED. Due to the fact that most of the literature we included was single-arm studies, it was imperative for future research to provide higher-quality evidence for validation.