Asiatic acid ameliorates doxorubicin-induced cardiotoxicity by promoting FPN-mediated iron export and inhibiting ferroptosis.

Doxorubicin (DOX), a common chemotherapeutic agent in cancer therapy, is accompanied by pronounced cardiotoxicity. Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity (DIC). Asiatic acid (AA), a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica, displays antioxidant, anti-inflammatory, and antiapoptotic activities. In this study, we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms. A chronic DIC model was established by challenging mice with DOX (5 mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25 mg·kg-1·d-1, i.g.). Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment. We showed that AA administration preserved cardiac function, significantly reduced cardiac injury, and improved cardiomyocyte contractile function in DIC mice. The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro. We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export, in a Nrf2-dependent manner. AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells. Moreover, AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385 (30 mg·kg-1·d-1, i.p.) administrated 30 min before AA in DIC mice. Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC, suggesting its therapeutic potential in the treatment of DIC.

Formal Syntheses of (-)-Quinocarcinamide and (-)-Quinocarcin.

Concise and scalable formal syntheses of (-)-quinocarcinamide and (-)-quinocarcin have been achieved in 9 steps with 9% overall yield from simple commercially available chemicals. The synthetic strategy features an ortho-regioselective Pictet-Spengler cyclization for the construction of the tetrahydroisoquinoline skeleton, a stereoselective formal intramolecular [3 + 2] cross cycloaddition of cyclopropane 1,1-diester with an imine for the construction of the 3,8-diazabicyclo[3.2.1]octane skeleton.

Methyltransferase DNMT3B promotes colorectal cancer cell proliferation by inhibiting PLCG2.

Aberrant DNA methylation patterns in the promoter region of PLCG2 are associated with dysregulated signaling pathways and cellular functions. Its role in colorectal cancer cells is still unknown. In this study, qRT-PCR is used to measure DNMT3B expression in colorectal cancer. Western blot analysis and immunohistochemistry are used to analyze DNMT3B and PLCG2 protein levels in colorectal tissues and cell lines. Cell Counting Kit-8 (CCK-8) and colony formation assays are used to assess the proliferation of colorectal cancer cells. Methylation-specific PCR (MSP) and bisulfite-sequencing PCR (BSP) are used to measure DNA methylation level. Our results show that DNMT3B is overexpressed in colorectal cells in the TCGA datasets according to Kaplan-Meier plots. DNMT3B is significantly overexpressed in tumor tissues compared to that in adjacent nontumor tissues. Western blot analysis results demonstrate high expression of DNMT3B in tumor tissues. Compared to normal colonic epithelial cells, colorectal cancer cell lines exhibit elevated level of PLCG2 methylation. Overexpression of PLCG2 effectively prevents the growth of colorectal cancer xenograft tumors in vivo. PLCG2 is identified as a key downstream regulatory protein of DNMT3B in colorectal cancer. DNMT3B inhibits PLCG2 transcription through methylation of the PLCG2 promoter region. DNMT3B controls colorectal cancer cell proliferation through PLCG2, which is useful for developing therapeutic approaches that target PLCG2 expression for the treatment of colorectal cancer.

Efficient adsorption of cationic dyes by a novel honeycomb-like porous hydrogel with ultrahigh mechanical property.

The optimization of hydrogel structure is crucial for adsorption capacity, mechanical stability, and reusability. Herein, a chitosan and laponite-XLS co-doped poly(acrylic acid-co-acrylamide) hydrogel (CXAA) with honeycomb-like porous structures is synthesized by cooperative cross-linking of 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) and laponite-XLS in reticular frameworks of acrylic acid (AAc) and acrylamide (AM). The CXAA exhibits extraordinary mechanical performances including tough tensile strength (3.36 MPa) and elasticity (2756 %), which facilitates recycling in practical adsorption treatment and broadens potential applications. Since the regular porous structures can fully expose numerous adsorption sites and electronegative natures within polymer materials, CXAA displays efficient and selective adsorption properties for cationic dyes like methylene blue (MB) and malachite green (MG) from mixed pollutants and can reach record-high values (MB = 6886 mg g-1, MG = 11,381 mg g-1) compared with previously reported adsorbents. Therefore, CXAA exhibits promising potential for separating cationic and anionic dyes by their charge disparities. Mechanism studies show that the synergistic effects of HACC, laponite-XLS, and functional groups in monomers promote highly efficient adsorption. Besides, the adsorption capacity of CXAA remains stable even after undergoing five cycles of regeneration. The results confirm that CXAA is a promising adsorbent for effectively removing organic dyes in wastewater.

Sorbitol metabolism plays a key role in the differential accumulation of sugar in two plum cultivars.

Sugar is vital for plant growth and determines fruit quality via its content and composition. This study explores the differential sugar accumulation in two plum varieties, 'Fengtangli (FTL)' and 'Siyueli (SYL)'. The result showed that 'FTL' fruit displayed higher soluble solids and sugar content at various development stages. Metabolomic analysis indicated increased sorbitol in 'FTL', linked to elevated sorbitol-6-phosphate-dehydrogenase (S6PDH) activity. Transcriptome analysis identified a key gene for sorbitol synthesis, PsS6PDH4, which was significantly higher expressed in 'FTL' than in 'SYL'. The function of the PsS6PDH4 gene was verified in strawberry, apple, and plum fruits using transient overexpression and virus-induced gene silencing techniques. The results showed that overexpression of the PsS6PDH4 gene in strawberry, apple, and plum fruits promoted the accumulation of soluble solids content and sorbitol, while inhibition of the gene reduced soluble solids content and sorbitol content. Meanwhile, analysis of the relationship between PsS6PDH4 gene expression, sorbitol, and soluble solids content in four different plum varieties revealed a significant correlation between PsS6PDH4 gene expression and soluble solids content as well as sorbitol content. This research discovered PsS6PDH4 as a crucial regulator of sugar metabolism in plum, with potential applications in improving fruit sweetness and nutritional value in various fruit species. Understanding these molecular pathways can lead to innovative approaches for enhancing fruit quality, benefiting sustainable agriculture and consumer preferences in the global fruit industry.

Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Investigation of piezoelectric printing devices for oil-free and on-demand picolitre monodisperse droplet generation.

Picolitre monodisperse droplet printing technology has important applications in biochemistry, such as accounting for quantitative analysis and single-cell analysis, and can be used for parallel high-throughput analysis of biomarkers and chemicals. However, commonly used droplet generation devices require complex control systems or customised microfluidic chips, making them costly and difficult for researchers to operate. Additionally, generating picolitre monodisperse droplets with microfluidic devices necessitates the introduction of an oil phase to block and separate the liquid. This requirement can reduce the throughput of the target droplets and cause cell contamination, hindering the adoption of this technology. By employing a common 1-mm-diameter capillary in the laboratory in combination with a piezoelectric transducer, we have achieved on-demand picolitre droplet printing of less than 100 pL in an oil-free environment. The device was found to be biocompatible with K562 cells. This approach is less costly, offers greater operational freedom, and is easier to integrate with other downstream assay modules or even handheld cell-printing devices. This study holds great potential for application in areas such as single-cell analysis, cell sampling, and pharmaceutical analysis.

Comparing cranial-caudal-medial and medial-lateral approaches for laparoscopic right hemicolectomy: a propensity score-matched analysis.

BACKGROUND: The cranial-caudal-medial approach (CCMA) has been proposed for laparoscopic right hemicolectomy nowadays. This study aimed to investigate the safety and oncological efficacy of CCMA in the treatment of right-sided colon cancer compared to the medial-lateral approach (MLA). METHODS: Patients diagnosed with right-sided colon cancer were included from February 2015 to June 2018, retrospectively, dividing into the CCMA group and the MLA group. We compared the basic characteristics and the short-term and long-term outcomes in two groups. RESULTS: Two hundred and ninety-six patients were included in this study. The baseline characteristics were similar in two groups. Compared with MLA group, CCMA group exhibited shorter operation time (136.3 ± 25.3 min vs. 151.6 ± 21.5 min, P < 0.001), lower estimated blood loss (44.1 ± 15.2 ml vs. 51.4 ± 26.9 min, P = 0.010), and more harvested lymph nodes (18.5 ± 7.1 vs. 16.5 ± 5.7, P = 0.021). The 5-year overall survival (OS) rate for the CCMA group was 76.5%, and the 5-year disease-free survival (DFS) rate was 72.3%, both of which were not inferior to the MLA group. No significant difference was found between two groups in terms of other clinical parameters. CONCLUSION: The CCMA in laparoscopic right hemicolectomy is safe and feasible, making the anatomical plane clearer. This approach can shorten the operation time, reduce intraoperative blood loss, harvest more lymph nodes, and yield satisfactory oncological outcomes.

Molecular Mechanisms and Therapeutic Targeting of Ferroptosis in Doxorubicin-Induced Cardiotoxicity.

Ferroptosis, an iron-dependent form of regulated cell death, has received increasing attention for its pathophysiologic contribution to the onset and development of doxorubicin-induced cardiotoxicity. Moreover, modulation of ferroptosis with specific inhibitors may provide new therapeutic opportunities for doxorubicin-induced cardiotoxicity. Here, we will review the molecular mechanisms and therapeutic promise of targeting ferroptosis in doxorubicin-induced cardiotoxicity.

Asian Screening Array and Next-Generation Sequencing Based Panels Applied to Preimplantation Genetic Testing for Monogenic Disorders Preclinical Workup in 294 Families: A Retrospective Analysis.

OBJECTIVE: Currently, the most commonly used methods for linkage analysis of pre-implantation genetic testing for monogenic disorders (PGT-M) are next generation sequencing (NGS) and SNP array. We aim to investigate whether the application efficacy of Asian screening array (ASA) in PGT-M preclinical workup for the Chinese population is superior to NGS based single nucleotide polymorphism (SNP) panels. METHODS: We conducted a retrospective analysis by reviewing 294 couples from a single center over the past 4 years and compared the detection results between NGS-based SNP panels and ASA. Using the numbers of informative SNPs upstream and downstream flanking of variants, we assessed the detection efficiency of both methods in monogenic diseases, chromosomal microdeletion syndrome and males with de novo variants, among other scenarios. RESULTS: Results indicate that ASA offers a greater number of informative SNPs compared with NGS-based SNP panels. Additionally, data analysis for ASA is generally more straightforward and may require less computational resources. While ASA can address most PGT-M challenges, we have also identified certain genes in previous tests that are not suitable for PGT-M using ASA. CONCLUSION: The application of ASA in PGT-M preclinical workup for Chinese populations has good practical value as it can perform linkage analysis for most genetic variants. However, for certain variants, NGS or other testing methods, such as mutated allele revealed by sequencing with aneuploidy and linkage analysis (MARSALA), may still be necessary for completion.

Study on quantitative generation technology of bio-fluorescence calibration particles based on inkjet generator.

Accurate measurements are critical for timely early warning and effective prevention of epidemics due to the continuing impact of bioaerosols on human health. In recent years, researchers have been focused on developing and calibrating online monitoring instruments. However, there is still a lack of laboratory-generated standard aerosol samples suitable for calibration. Therefore, in this study, we utilized a self-developed Ink Jet Aerosol Generator (H-IJAG) to achieve controllable generation of monodisperse aerosol standard particles. The Aerosol Particle Size Spectrometer (APSS, TOPAS 323) was employed as the particle detector. The diameter of the droplet was calculated by measuring the projected area of the droplet in the same image using Image-J software. Experimental results demonstrated that under standardized inkjet parameters, H-IJAG exhibited good reliability and reproducibility, and generated solid particles within (0.4-15) µm. To better simulate the laser-induced fluorescence emission properties of ambient bioaerosol, tryptophan (Trp) and 7-hydroxycoumarin-4-acetic acid (7-HCA) were selected as solutes of the laboratory-generated aerosol samples, which are known bio-fluorescent materials. According to the law of propagation of uncertainty, the relative uncertainty of the volume equivalent diameter of Trp and 7-HCA solid particles by H-IJAG were 0.42 %, while the relative uncertainty of the particle number concentrations of Trp and 7-HCA solid particles generated by H-IJAG were 1.4 %. This optimized IJAG technique provides a promising solution for the accurate calibration of bioaerosol monitors.

Effect of cetuximab plus FOLFOX4 regimen on clinical outcomes in advanced gastric carcinoma patients receiving evidence-based care.

BACKGROUND: Although chemotherapy is effective for treating advanced gastric carcinoma (aGC), it may lead to an adverse prognosis. Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients. AIM: To determine the efficacy and safety of cetuximab (CET) combined with the FOLFOX4 regimen (infusional fluorouracil, folinic acid, and oxaliplatin) as first-line therapy for patients with aGC, who received evidence-based care (EBC). METHODS: A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled. Of these, 60 in the research group (RG) received CET + FOLFOX4 as first-line therapy, whereas 57 in the control group (CG) received FOLFOX4. The efficacy [clinical response rate (RR) and disease control rate (DCR)], safety (liver and kidney dysfunction, leukopenia, thrombocytopenia, rash, and diarrhea), serum tumor marker expression [STMs; carbohydrate antigen (CA) 19-9, CA72-4, and carcinoembryonic antigen (CEA)], inflammatory indicators [interleukin (IL)-2 and IL-10], and quality of life (QOL) of the two groups were compared. RESULTS: A markedly higher RR and DCR were observed in the RG compared with the CG, with an equivalent safety profile between the two groups. RG exhibited notably reduced CA19-9, CA72-4, CEA, and IL-2 levels following treatment, which were lower than the pre-treatment levels and those in the CG. Post-treatment IL-10 was statistically increased in RG, higher than the pre-treatment level and the CG. Moreover, a significantly improved QOL was evident in the RG. CONCLUSION: The CET + FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC. It facilitates the suppression of STMs, ameliorates the serum inflammatory microenvironment, and enhances QOL, without increased adverse drug effects.

A mitochondria-targeted fluorescent probe for discrimination of biothiols by dual-channel imaging in living cells and zebrafish.

Biothiols, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play distinct yet crucial roles in various mitochondrial physiological activities. However, due to their similar chemical structures, distinguishing and detecting Cys/Hcy/GSH poses a considerable challenge. In this study, we developed a dual-channel, mitochondrial-targeted fluorescent probe termed QX-NBD, designed specifically for discriminating Cys/Hcy from GSH. The incorporation of a quinolinium group endowed the probe with excellent mitochondrial targeting capabilities. This functionality arose from the positively charged group's ability to selectively bind to negatively charged mitochondrial membranes through electrostatic interactions. Additionally, the ether bond between 4-chloro-7-nitro-1,2,3-benzoxadiazole and the near-infrared fluorophore QX-OH rendered the probe susceptible to nucleophilic attack by biothiols. Upon the introduction of Cys/Hcy, the probe exhibited dual fluorescence emissions in red and green. Conversely, the presence of GSH resulted in only red fluorescence emission. The detection limits of the probe for Cys and Hcy at 542 nm in buffer solution were determined to be 0.044 µM and 0.042 µM, respectively. Similarly, the detection limit for all these biothiols was 0.028 µM at 678 nm. Furthermore, the response times for Cys/Hcy/GSH were recorded as 4.0 min, 5.5 min, and 9.5 min, respectively. Moreover, the probe was employed to monitor fluctuations in biothiol levels during oxidative stress in both HeLa cells and zebrafish, demonstrating its applicability and utility in biological contexts.

RIP3 orchestrates oxidative stress and pyroptosis in doxorubicin-induced cardiotoxicity through regulation of AKT/Nrf2 signaling cascade.

This study was designed to explore the role of RIP3 in DOX-induced cardiotoxicity and its underlying molecular mechanisms. Our results demonstrate that RIP3 exacerbates DOX-induced cardiotoxicity through promoting oxidative stress and pyroptosis by regulating the AKT/Nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway. Inhibition of RIP3 using GSK-872 attenuated DOX-induced cardiac remodeling and contractile dysfunction. Moreover, using GSK-872 in vivo, the results revealed that inhibition of RIP3 alleviated DOX-induced cardiotoxicity by the resulting inhibition of oxidative stress and pyroptosis. In addition, inhibition of RIP3 increased the protein levels of AKT and Nrf2 in DOX-treated mouse hearts. Furthermore, the AKT inhibitor LY294002 lessened RIP3 reduction-offered protection against DOX-induced H9c2 cell injury by moderating oxidative stress and pyroptosis. Taken together, these data demonstrate that RIP3 activation orchestrates DOX-induced cardiotoxicity through elevated oxidative stress and pyroptosis in an AKT/Nrf2-dependent manner. Those findings highlight the clinical relevance and therapeutic potential of targeting RIP3 for the treatment of DOX-induced cardiotoxicity.

Qualifying Event and Recurrence of Ischemic Stroke in Symptomatic Artery Occlusion: A Post Hoc Analysis of CMOSS.

BACKGROUND: The authors aimed to elucidate the relationship between latest ischemic event and the incidence of subsequent ischemic stroke in patients with symptomatic artery occlusion. METHODS AND RESULTS: We analyzed the association between qualifying event-the latest ischemic event (transient ischemic attack [TIA] or stroke)-and the incidence of ipsilateral ischemic stroke in patients with symptomatic artery occlusion treated with medical therapy alone in CMOSS (Carotid or Middle Cerebral Artery Occlusion Surgery Study). The incidence of CMOSS primary outcomes, including any stroke or death within 30 days after randomization or ipsilateral ischemic stroke between 30 days and 2 years, between the bypass surgical and medical groups, stratified by qualifying events, was also compared. Of the 165 patients treated with medical therapy alone, 75 had a TIA and 90 had a stroke as their qualifying event. The incidence of ipsilateral ischemic stroke did not significantly differ between patients with a TIA and those with a stroke as their qualifying event (13.3% versus 6.7%, P=0.17). In multivariate analysis, the qualifying event was not associated with the incidence of ipsilateral ischemic stroke. There were no significant differences in the CMOSS primary outcomes between the surgical and medical groups, regardless of the qualifying event being TIA (10.1% versus 12.2%, P=0.86) or stroke (6.7% versus 8.9%, P=0.55). CONCLUSIONS: Among patients with symptomatic artery occlusion and hemodynamic insufficiency, the risk of subsequent ipsilateral ischemic stroke does not appear to be lower in patients presenting with a TIA compared with those with a stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01758614.

A prognostic nomogram to predict the cancer-specific survival of patients with initially diagnosed metastatic gastric cancer: a validation study in a Chinese cohort.

BACKGROUND: Few studies have been designed to predict the survival of Chinese patients initially diagnosed with metastatic gastric cancer (mGC). Therefore, the objective of this study was to construct and validate a new nomogram model to predict cancer-specific survival (CSS) in Chinese patients. METHODS: We collected 328 patients with mGC from Northern Jiangsu People's Hospital as the training cohort and 60 patients from Xinyuan County People's Hospital as the external validation cohort. Multivariate Cox regression was used to identify risk factors, and a nomogram was created to predict CSS. The predictive performance of the nomogram was evaluated using the consistency index (C-index), the calibration curve, and the decision curve analysis (DCA) in the training cohort and the validation cohort. RESULTS: Multivariate Cox regression identified differentiation grade (P < 0.001), T-stage (P < 0.05), N-stage (P < 0.001), surgery (P < 0.05), and chemotherapy (P < 0.001) as independent predictors of CSS. Nomogram of chemotherapy regimens and cycles was also designed by us for the prediction of mGC. Thus, these factors are integrated into the nomogram model: the C-index value was 0.72 (95% CI 0.70-0.85) for the nomogram model and 0.82 (95% CI 0.79-0.89) and 0.73 (95% CI 0.70-0.86) for the internal and external validation cohorts, respectively. Calibration curves and DCA also demonstrated adequate fit and ideal net benefit in prediction and clinical applications. CONCLUSIONS: We established a practical nomogram to predict CSS in Chinese patients initially diagnosed with mGC. Nomograms can be used to individualize survival predictions and guide clinicians in making therapeutic decisions.

Inhibition of ER stress using tauroursodeoxycholic acid rescues obesity-evoked cardiac remodeling and contractile anomalies through regulation of ferroptosis.

Interrupted ER homeostasis contributes to the etiology of obesity cardiomyopathy although it remains elusive how ER stress evokes cardiac anomalies in obesity. Our study evaluated the impact of ER stress inhibition on cardiac anomalies in obesity. Lean and ob/ob obese mice received chemical ER chaperone tauroursodeoxycholic acid (TUDCA, 50 mg/kg/d, p.o.) for 35 days prior to evaluation of glucose sensitivity, echocardiographic, myocardial geometric, cardiomyocyte mechanical and subcellular Ca2+ property, mitochondrial integrity, oxidative stress, apoptosis, and ferroptosis. Intracellular Ca2+ governing domains including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) were monitored by45Ca2+uptake and immunoblotting. Our results noted that TUDCA alleviated myocardial remodeling (fibrosis, hypertrophy, enlarged LVESD), echocardiographic anomalies (compromised fractional shortening and ejection fraction), cardiomyocyte contractile dysfunction (amplitude and velocity of cell shortening, relengthening time) and intracellular Ca2+ anomalies (compromised subcellular Ca2+ release, clearance and SERCA function), mitochondrial damage (collapsed membrane potential, downregulated mitochondrial elements and ultrastructural alteration), ER stress (GRP78, eIF2α and ATF4), oxidative stress, apoptosis and ferroptosis [downregulated SLC7A11, GPx4 and upregulated transferrin receptor (TFRC)] without affecting global glucose sensitivity and serum Fe2+ in obese mice. Obesity-evoked change in HSP90, phospholamban and Na+-Ca2+ exchanger was spared by the chemical ER chaperone. Moreover, in vitro results noted that TUDCA, PERK inhibitor GSK2606414, TFRC neutralizing antibody and ferroptosis inhibitor LIP1 mitigated palmitic acid-elicited changes in lipid peroxidation and mechanical function. Our findings favored a role for ferroptosis in obesity cardiomyopathy downstream of ER stress.

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. METHODS: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. RESULTS: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. CONCLUSION: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

Efficacy and safety of antibody-drug conjugates in the treatment of urothelial cell carcinoma: a systematic review and meta-analysis of prospective clinical trials.

Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody-drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases. Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses. Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%). Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232.

Analysis of Clinical Efficacy and Quality of Life of Braun Anastomosis in Gastrointestinal Reconstruction in Totally Laparoscopic Distal Gastrectomy: A Single-Center Retrospective Study.

OBJECTIVE: This study aimed to compare the clinical efficacy and quality of life of B-IIB (Billroth-II with Braun anastomosis) and B-II (Billroth-II anastomosis) in the alimentary tract reconstruction postoperative totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. METHODS: From February 2016 to January 2022, 158 patients underwent totally laparoscopic distal gastrectomy and D2 lymphadenectomy in Northern Jiangsu People's Hospital, with Billroth-II with Braun anastomosis for 93 patients and Billroth-II anastomosis for 65 patients. The patients' data were collected prospectively and reviewed retrospectively. RESULTS: In this study, the post-op hospital stay of B-IIB group were shorter than B-II group (12.70 ± 3.08 days in the B-IIB group versus 14.12 ± 4.90 days in the B-II group, p < 0.05) and the first post-op flatus time of the B-IIB group were shorter than B-II group (3.49 ± 1.02 days versus 4.08 ± 1.85 days, p < 0.05). Two groups did differ significantly in hemoglobin on postoperative 3 months, albumin at 3 months after operation, and serum sodium on postoperative 3 days and 3 months (p < 0.05), and the B-IIB had an advantage; the complications incidence (Clavien-Dindo grade II or even a higher grade) of the B-IIB group and B-II group were 10.75% and 29.23%, respectively. There being a statistical difference between the two groups. The B-IIB group and the B-II group both had different degrees of weight loss at 3 months after operation compared with preoperative weight. The weight of B-IIB group was 4.04 ± 1.33 kg, which was less than B-II group (8.08 ± 1.47 kg). The difference was statistically significant (p < 0.05). According to the PGSAS (Postgastrectomy Syndrome Assessment Scale), the score of the B-IIB group is lower than that of the B-II group for esophageal reflux gastritis, dyspepsia, and dumping syndrome group (1.84 ± 0.92 VS 2.15 ± 0.85, P = 0.031; 1.86 ± 1.10 VS 2.22 ± 0.91, P = 0.034; 1.98 ± 1.06 VS 2.32 ± 0.94, P = 0.037, respectively). CONCLUSION: Totally laparoscopic distal gastrectomy with Billroth-II Braun reconstruction is a safe and technically feasible method for gastric cancer patients, which can reduce the incidence of postoperative reflux esophagitis and dumping syndrome. Compared with Billroth-II reconstruction, it has advantages in maintaining postoperative nutritional status and electrolyte balance and improving quality of life.