Regulation of post-translational modification of PD-L1 and associated opportunities for novel small-molecule therapeutics.

PD-L1 is overexpressed on the surface of tumor cells and binds to PD-1, resulting in tumor immune escape. Therapeutic strategies to target the PD-1/PD-L1 pathway involve blocking the binding. Immune checkpoint inhibitors have limited efficacy against tumors because PD-L1 is also present in the cytoplasm. PD-L1 of post-translational modifications (PTMs) have uncovered numerous mechanisms contributing to carcinogenesis and have identified potential therapeutic targets. Therefore, small molecule inhibitors can block crucial carcinogenic signaling pathways, making them a potential therapeutic option. To better develop small molecule inhibitors, we have summarized the PTMs of PD-L1. This review discusses the regulatory mechanisms of small molecule inhibitors in carcinogenesis and explore their potential applications, proposing a novel approach for tumor immunotherapy based on PD-L1 PTM.

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Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action.

Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 = 0.87 µM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.

Discovery and biological evaluation of biaryl acetamide derivatives as selective and in vivo active sphingosine kinase-2 inhibitors.

Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer.

Modulators for palmitoylation of proteins and small molecules.

As an essential form of lipid modification for maintaining vital cellular functions, palmitoylation plays an important role in in the regulation of various physiological processes, serving as a promising therapeutic target for diseases like cancer and neurological disorders. Ongoing research has revealed that palmitoylation can be categorized into three distinct types: N-palmitoylation, O-palmitoylation and S-palmitoylation. Herein this paper provides an overview of the regulatory enzymes involved in palmitoylation, including palmitoyltransferases and depalmitoylases, and discusses the currently available broad-spectrum and selective inhibitors for these enzymes.

Mitophagy in neurodegenerative disease pathogenesis.

Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Progression of Gastrointestinal Injury During Antiplatelet Therapy After Percutaneous Coronary Intervention: A Secondary Analysis of the OPT-PEACE Randomized Clinical Trial.

Importance: Gastrointestinal injury progression induced by antiplatelet therapy in patients after percutaneous coronary intervention (PCI) has not been well studied. Objective: To assess the association of aspirin, clopidogrel, and their combination with gastrointestinal injury progression among patients without high bleeding risk after PCI. Design, Setting, and Participants: This secondary analysis assessed data from the Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by ANKON Magnetically Controlled Capsule Endoscopy (OPT-PEACE) double-masked, placebo-controlled, multicenter randomized clinical trial. The OPT-PEACE trial was conducted at 28 centers in China, and recruitment took place from July 13, 2017, to July 13, 2019. The trial included patients with stable coronary artery disease or acute coronary syndromes without ST-segment elevation after PCI. Statistical analysis was conducted from September 13, 2022, to January 23, 2023. Interventions: Patients underwent magnetically controlled capsule endoscopy (MCE) at baseline and after 6 months of dual antiplatelet therapy (DAPT) with aspirin (100 mg/d) plus clopidogrel (75 mg/d). Those with no evidence of gastrointestinal ulcers or bleeding (ie, the intention-to-treat [ITT] cohort) were randomized (1:1:1) to aspirin (100 mg/d) plus matching placebo (aspirin alone), clopidogrel (75 mg/d) plus matching placebo (clopidogrel alone), or DAPT for an additional 6 months. A third MCE was performed 12 months after PCI. Main Outcomes and Measures: The primary outcome was the rate of gastric injury progression as assessed with the results of the 3 MCEs (at baseline, 6 months, and 12 months) in the modified intention-to-treat (mITT) population. The key secondary outcome was the rate of small-intestinal injury progression. Gastric or small-intestinal injury progression was defined as a quantitative increase in erosions or ulcers between the second and third MCEs (at 6 and 12 months, respectively). Results: This study included the 394 patients in the mITT cohort. Their mean (SD) age was 56.9 (8.7) years, and most were men (296 [75.1%]). A total of 132 patients were randomized to aspirin alone, 132 to clopidogrel alone, and 130 to DAPT. Gastric injury progression occurred in 49 aspirin users (37.1%), 64 clopidogrel users (48.5%), and 69 DAPT users (53.1%) (P = .02), reflecting a lower rate of gastric injury progression among aspirin users vs DAPT users (risk ratio [RR], 0.70 [95% CI, 0.49-0.99]; P = .009). No significant difference was observed between clopidogrel alone and DAPT (48.5% vs 53.1%; P = .46) or between aspirin alone and clopidogrel alone (37.1% vs 48.5%; P = .06). A total of 51 aspirin users (38.6%), 65 clopidogrel users (49.2%), and 71 DAPT users (54.6%) (P = .03) developed progressive small-intestinal injury, reflecting a lower rate of small-intestinal injury among aspirin users vs DAPT users (RR, 0.71 [95% CI, 0.50-0.99]; P = .01). No difference was observed between patients treated with clopidogrel vs DAPT (49.2% vs 54.6%; P = .38) or with aspirin vs clopidogrel (38.6% vs 49.2%; P = .08). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ongoing use of aspirin, clopidogrel, or their combination between 6 and 12 months after PCI was associated with progressive gastric and small-intestinal injury in a substantial proportion of patients, more so with DAPT than with monotherapy. Clopidogrel was at least as likely as aspirin to induce gastrointestinal injury progression. Future research is warranted to determine what impact the findings from MCEs would have on decision-making of antiplatelet therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03198741.

( ±)-Dibrevianamides Q1 and Q2, the key precursors of asperginulin A from a marine-derived fungus.

Two pairs of new dimeric diketopiperazine alkaloids, ( ±)-dibrevianamides Q1 and Q2 (( ±)-1 and ( ±)-2), together with seven previously reported analogues (( ±)-3, 4-6, and ( ±)-7) were obtained from a marine-derived fungus Aspergillus sp. The structures of ( ±)-1 and ( ±)-2 were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. Speculated from the biogenesis, ( ±)-dibrevianamides Q1 and Q2 (( ±)-1 and ( ±)-2) might be the key precursor of [2 + 2] diketopiperazine dimers (( ±)-3). Compounds ( +)-1 and ( -)-2 displayed anti-H1N1 virus activity with IC50 values of 12.6 and 19.5 µM. Compound ( +)-1 showed significant activity against Mycobacterium tuberculosis (MIC, 10.2 µg/mL). KEY POINTS: • Two pairs of new dimeric diketopiperazine alkaloids were obtained from the marine-derived fungus Aspergillus sp. • The structures of the new compounds were clarified using comprehensive spectroscopic analyses, the calculated ECD, and DP4 + probability methods. • ( ±)-Dibrevianamides Q1 and Q2 were speculated to be the key precursor of [2 + 2] diketopiperazine dimers ( ±)-asperginulin A.

Design, synthesis, antitumor activity, and molecular dynamics simulations of novel sphingosine kinase 2 inhibitors.

Targeting sphingosine kinase 2 (SphK2) has become a novel strategy for the treatment of cancer. However, potent and selective SphK2 inhibitors are rare. In our work, a series of novel SphK2 inhibitors were innovatively designed, synthesized and screened. Compound 12e showed the best inhibitory activity. Molecular dynamics simulations were carried out to analyze the detailed interactions between the SphK2 and its inhibitors. Moreover, 12e exhibited anti-proliferative activity in various cancer cells, and inhibited the migration of human breast cancer cells MCF-7.

A time-series analysis of short-term ambient ozone exposure and hospitalizations from acute myocardial infarction in Henan, China.

Epidemiological studies in recent years have identified an association between exposure to air pollutants and acute myocardial infarction (AMI); however, the association between short-term ozone (O3) exposure and AMI hospitalization remains unclear, particularly in developing countries. Therefore, this study collected information on 24,489 AMI patients, including daily air pollutant and meteorological data in Henan, China, between 2016 and 2021. A distributed lagged nonlinear model combined with a Poisson regression model was used to estimate the nonlinear lagged effect of O3 on AMI hospitalizations. We also quantified the effects of O3 on the number of AMI hospitalizations, hospitalization days, and hospitalization costs. The results showed that single- and dual-pollution models of O3 at lag0, lag1, and lag (01-07) were risk factors for AMI hospitalizations, with the most significant effect at lag03 (RR = 1.132, 95% CI:1.083-1.182). Further studies showed that males, younger people (15-64 years), warm seasons, and long sunshine duration were more susceptible to O3. Hospitalizations attributable to O3 during the study period accounted for 11.66% of the total hospitalizations, corresponding to 2856 patients, 33,492 hospital days, and 90 million RMB. Maintaining O3 at 10-130 µg/m3 can prevent hundreds of AMI hospitalizations and save millions of RMB per year in Henan, China. In conclusion, we found that short-term exposure to O3 was significantly associated with an increased risk of hospitalization for AMI in Henan, China, and that further reductions in ambient O3 levels may have substantial health and economic benefits for patients and local healthcare facilities.

Discovery and Validation of Novel Genes in a Large Chinese Autism Spectrum Disorder Cohort.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes impairments in social communication and stereotypical behaviors, often accompanied by developmental delay or intellectual disability. A growing body of evidence suggests that ASD is highly heritable, and genetic studies have defined numerous risk genes. However, most studies have been conducted with individuals of European and Hispanic ancestry, and there is a lack of genetic analyses of ASD in the East Asian population. METHODS: We performed whole-exome sequencing on 772 Chinese ASD trios and combined the data with a previous study of 369 Chinese ASD trios, identifying de novo variants in 1141 ASD trios. We used single-cell RNA sequencing analysis to identify the cell types in which ASD-related genes were enriched. In addition, we validated the function of a candidate high-functioning autism gene in mouse models using genetic approaches. RESULTS: Our findings showed that ASD without developmental delay or intellectual disability carried fewer disruptive de novo variants than ASD with developmental delay or intellectual disability. Moreover, we identified 9 novel ASD candidate genes that were not present in the current ASD gene database. We further validated one such novel ASD candidate gene, SLC35G1, by showing that mice harboring a heterozygous deletion of Slc35g1 exhibited defects in interactive social behaviors. CONCLUSIONS: Our work nominates novel ASD candidate genes and emphasizes the importance of genome-wide genetic studies with ASD cohorts of different ancestries to reveal the comprehensive genetic architecture of ASD.

A novel classification, management and long-term outcomes of coronary artery involvement in acute aortic dissection.

BACKGROUND: To introduce a new and simple classification and management of coronary artery involvement in aortic dissection and report results. METHODS: Coronary artery involvement was classified into two types according to the integrity of coronary intima: simple lesion (type S) and complex lesion (type C). Complex lesions were treated by CABG and simple lesions were treated by ostial repair or reimplantation. Data were collected and analyzed retrospectively. RESULTS: From January 2010 to December 2019, 267 consecutive patients were enrolled in the study, and among them complex lesions occurred in 27 patients (11.1%) and simple lesions was found in 240 patients(89.9%). Eleven untreated vessels with simple lesion were found to be involved again in the same operation and treated by CABG. The two type groups had comparable operative mortality (type S vs. type C, 9.6% vs. 18.5%, P = 0.28). 221 patients received follow-up with a median duration of 52 months. The overall survival rates at 1, 5, and 10 years postoperatively were 88.9%, 85.7%, and 79.8% in type S group and 79.2%, 79.2%, and 79.2% in type C group, respectively (P = 0.47). For the patients who received CABG and survived at discharge, radiographic follow-up with a median duration of 28 (IQR 7-55.5) months showed the freedom from occlusion of vein graft at 1, 5, and 10 years postoperatively were 87.5%, 70.0%, 28.0%. CONCLUSIONS: According to the new classification, two types of lesions could be treated by corresponding methods with satisfactory early and long-term results. Unrepaired coronary artery was at a risk of re-involvement. Vein graft onto arteries without atherosclerosis still had a high occlusion rate.

Design and synthesis of a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD.

It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress, therefore anti-inflammatory and antioxidant bifunctional agents may interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, have been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a good strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound to design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoisoflavonoids, aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant pharmacophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram, roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities in reducing Fe3+ and complexing Fe2+. 6o, as the candidate anti-inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, Distribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg and 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-α in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.

Design, synthesis and biological activity evaluation of novel covalent S-acylation inhibitors.

In order to obtain diverse S-acylation inhibitors and address the defects of existing S-acylation inhibitors, a series of novel covalent S-acylation inhibitors are designed through synthesis. According to the results of MTT assay, most compounds produce a better anti-proliferation effect on MCF-7, MGC-803 and U937 cell lines than 2-BP. Among them, 8d, 8i, 8j and 10e exert a significant inhibitory effect on MCF-7 cell, with the IC50 values falling below 20 µM. Besides, the toxic effects of some compounds on 3T3 cell line are less significant than 2-BP. According to the results of acyl-biotin exchange (ABE) experiment, most of them could inhibit S-acylation, and 8i performs best in this respect, with the inhibitory rate reaching 89.3% at the concentration of 20 µM. The results of molecular docking show the conjugation of 8i with surrounding amino acids. Additionally, 8i could not only suppress the migration of MCF-7 cell line, but also cause it to stagnate in G0/G1 phase, thus promoting cell apoptosis.

Design, synthesis and biological evaluation of dual Topo II/HDAC inhibitors bearing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs.

Both topoisomerase II (Topo II) and histone deacetylase (HDAC) are important therapeutic targets for cancer. In this study, two series of novel compounds containing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs were designed and synthesized as dual Topo II/HDAC inhibitors. MTT assay indicated that all the compounds displayed potential antiproliferative activity against three cancer cell lines (MGC-803, MCF-7 and U937) and low cytotoxicity on normal cell line (3T3). In the enzyme activity inhibition experiments, compounds 7d and 8d exhibited excellent dual inhibitory activities against Topo II and HDAC. Cleavage reaction assay showed that 7d was a Topo II poison, which was consistent with the docking results. Further experimental results revealed that compounds 7d and 8d could promote apoptosis and significantly inhibit the migration in MCF-7 cells. Molecular docking showed that compounds 7d and 8d bind Topo II and HDAC at the active sites. Molecular dynamics simulation showed that 7d can stably bind to Topo II and HDAC.

Discovery of Novel N-Hydroxy-1,2,4-oxadiazole-5-formamides as ASM Direct Inhibitors for the Treatment of Atherosclerosis.

Acid sphingomyelinase (ASM), which regulates sphingolipid metabolism and lipid signaling, has been considered as a new potential target for the treatment of atherosclerosis. In this study, a series of benzene-heterocyclic-based ASM inhibitors were rationally designed, synthesized, and screened for the first time. As a result, some compounds showed favorable inhibitory activity against recombinant human ASM. The detailed SARs are also discussed. Compound 4i revealed good pharmacokinetic data and in vivo inhibitory activity against ASM by reducing the level of ceramide in mice plasma and liver. Pharmacodynamic studies confirmed that 4i could lessen lipid plaques in the aortic arch and aorta and reduce plasma ceramide concentration and Ox-LDL levels. Moreover, 4i was found to significantly decrease LPS-induced and Ox-LDL-induced cell inflammation by regulating the levels of ceramide and sphingomyelin. Overall, this study preliminarily demonstrates that ASM may be an effective target against atherosclerosis for the first time.

Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents.

A series of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine were designed and synthesized with improved anti-hepatocellular carcinoma (HCC) activities. The optimal compound 4d showed strong activities against HepG2, Sk-Hep-1, Huh-7 and Hep3B cells with IC50 values of 0.58-1.15 µM, which were superior to positive reference cisplatin. Interestingly, 4d exhibited over 40-fold more potent activity against cisplatin-resistant HepG2/DPP cells while showing lower cytotoxicity in normal LX-2 cells. The mechanism studies revealed 4d greatly stabilized G-quadruplex DNA leading to intracellular c-MYC expression downregulation, blocked G2/M-phase cell cycle by affecting related p-cdc25c, cdc2 and cyclin B1 expressions, and induced apoptosis by a ROS-promoted PI3K/Akt-mitochondrial pathway. Furthermore, 4d possessed good pharmacokinetic properties and significantly inhibited the tumor growth in the H22 liver cancer xenograft mouse model without obvious toxicity. Altogether, the remarkably biological profiles of 4d both in vitro and in vivo would make it a promising candidate for HCC therapy.

Sappanone A: A natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the heartwood of Caesalpinia sappan L.

ETHNOPHARMACOLOGICAL RELEVANCE: Sumu (Lignum sappan), the dry heartwood of Caesalpinia sappan L., is a traditional Chinese medicine used as an analgesic and anti-inflammatory agent. AIM OF THE STUDY: The study aspired to discover natural phosphodiesterase 4 (PDE4) inhibitors with dual anti-inflammatory and antioxidant activities from Sumu for the treatment of chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: To accurately and efficiently identify natural PDE4 inhibitors from Sumu, molecular docking and molecular dynamics (MD) analysis methods were used for structure-based virtual screening of a self-built database of primary polyphenols in Sumu. According to the previous studies of Sumu and the free radical scavenging mechanism of polyphenols, the reported antioxidant components from Sumu and the potential antioxidants with the antioxidant pharmacophore of catechol and π-conjugated moieties were selected from the potential PDE4 inhibitors predicted by docking. Sappanone A, a potential PDE4 inhibitor with antioxidant activity from Sumu, was selected, calculated and synthesized to evaluate its dual anti-inflammatory and antioxidant functions in vitro and in vivo studies. Herein sappanone A was assayed for its inhibitory effects against PDE4 enzyme activity, tumor necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate; sappanone A was also assayed for its abilities of radical (DPPH) scavenging, reducing Fe3+ and complexing Fe2+ in vitro. Additionally, LPS-induced acute lung injury (ALI) in mice was used to evaluate its anti-inflammatory activity as a PDE4 inhibitor in vivo, and the levels of TNF-α and total protein in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung were assayed. RESULTS: The present study predicted and validated that sappanone A was a promising PDE4 inhibitor from Sumu with dual anti-inflammation and antioxidant activities from Sumu. In vitro, sappanone A remarkably inhibited PDE4 enzyme activity and reduced TNF-α production induced by LPS in RAW264.7 macrophages and MDA production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities of scavenging DPPH radicals, reducing Fe3+ and complexing Fe2+. In vivo, sappanone A (25 mg/kg and 50 mg/kg, i.p., twice daily for 7 days) distinctly prevented LPS-induced ALI in mice by reducing the levels of TNF-α and total protein in BALF and MPO activity in the lung. CONCLUSION: Sappanone A is a natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the traditional Chinese medicine Sumu, which may be a promising therapeutic agent to prevent the vicious cycle of COPD inflammation and oxidative stress.

Visceral protection in total arch replacement for aortic dissection: Effect of lower body hypothermia.

OBJECTIVE: Optimal hypothermia strategy for total arch replacement in acute type A aortic dissection (ATAAD) is unclear. A higher temperature during circulatory arrest might reduce tolerance to ischemia for visceral organs. We sought to investigate the effect of hypothermia on visceral protection. METHODS: From January 2010 to December 2019, 1138 consecutive patients underwent total arch replacement combined with frozen elephant trunk for acute type A aortic dissection. The data were retrospectively collected and analyzed. Visceral organ injury and visceral-related adverse outcomes were defined as acute renal failure or spinal cord injury or both. Multivariate logistic regression analysis and multivariate linear regression model were used. RESULTS: The mean age of patient was 46.9 ± 10.0 years, with a male preponderance (79.6%). Operative mortality was 6.1% (69 patients). Spinal cord injury occurred in 55 (4.8%) patients and 133 (11.7%) patients had acute renal failure. In the multivariate logistic regression model, neither bladder temperature (odds ratio [OR] 0.971, 95% confidence interval [CI] 0.922-1.024, p = .278) nor circulatory arrest duration (OR 1.017, 95% CI 0.987-1.047, p = .267) significantly associated with visceral-related adverse outcomes. Female, lower limb malperfusion, age, cardiopulmonary bypass (CPB) duration and preoperative serum creatinine level were independent risk factors of visceral-related outcomes. There was a significant negative correlation between bladder temperature and CPB duration in multiple linear regression model (ß = -3.67, p < .0001). CONCLUSIONS: Bladder temperature had no effect on outcomes related to visceral protection under the premise of short circulatory arrest duration, but female gender, lower limb malperfusion, age, CPB duration, and preoperative serum creatinine level were independent risk factors. Bladder temperature negatively correlated to CPB duration.

Comparison of seven cyclosporine A formulations for dry eye disease: A systematic review and network meta-analysis.

Background: Dry eye disease is a common ocular surface disease affecting tens of millions of people worldwide. It is characterized by an unstable tear film and increasing prevalence. Different commercial formulations of cyclosporine A for dry eye have been approved, however, it is still unclear whether the differences in formulations of these products will make a difference in clinical efficacy and safety. Methods: Randomized controlled trials of commercial cyclosporine A formulation for dry eye disease were searched in Pubmed, EMBASE, Scopus, and Cochrane controlled trials registries and Web of Science from inception till 1 December 2021. Independent literature screening, data extraction, quality evaluation, and the study in line with quality standards were analyzed by using Stata16.0 software. The study is registered with PROSPERO under the number CRD42022301423. Code and data for this study is publicly available (https://github.com/DongYangGao/Dongyang.github.io.git). Results: 21 randomized clinical trials with a total of 4,107 participants were included in this study. Restasis® (OR-4.82, 95% CI-6.18 to 3.45, SUCRA 77.2%) was the most effective commercial formulation for reducing OSDI, Zirun® (SUCRA 73.9%) performed better in improving Schirmer's test. TJ Cyporin® (SUCRA 65.3%) ranked first in terms of improving tear film break-up time. For treatment-emergent adverse events incidence, Clacier® was close to placebo. The risk of reporting bias is considered low. Conclusion: In the comparison of outcomes included in this study, the optimal order of various commercial cyclosporine A formulations is different, so it is difficult to select the optimal formula. Appropriate commercial formulations should be selected according to patients' conditions in clinical practice.