Anesthesia with ciprofol in cardiac surgery with cardiopulmonary bypass:A case report

BACKGROUND Ciprofol is a novel agent for intravenous general anesthesia.In February 2022,it was approved by the National Medical Products Administration for general anesthesia induction and maintenance.It has the advantages of fast onset,fast elimination,stable circulation,and few adverse reactions.However,the efficacy and safety of ciprofol in cardiac surgery with cardiopulmonary bypass have not been reported.Here we describe a case where ciprofol was successfully used for anesthesia in cardiac surgery with cardiopulmonary bypass.CASE SUMMARY A 72-year-old man(height 176 cm;weight 70 kg)was diagnosed with coronary atherosclerotic cardiomyopathy requiring coronary artery bypass grafting and left ventricular aneurysmectomy.Ciprofol was administered for induction(0.4 mg/kg)and maintenance(0.6-1.0 mg/kg/h)of general anesthesia.During the entire operation,the bispectral index,hemodynamics,and blood oxygen saturation were maintained at normal levels.The patient recovered well after surgery,with no serious adverse events related to ciprofol.CONCLUSION Ciprofol is safe and effective for anesthesia in cardiac surgery with cardiopulmonary bypass.

Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofissionassociated cell death(MFAD)by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy.By screening a series of paninhibitors,we identified pracinostat,a pan-histone deacetylase(HDAC)inhibitor,as a novel MFAD inducer,that exhibited a significant anticancer effect on colorectal cancer(CRC)in vivo and in vitro.Pracinostat increased the expression of cyclin-dependent kinase 5(CDK5)and induced its acetylation at residue lysine 33,accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynaminrelated protein 1(Drp1)-mediated mitochondrial peripheral fission.CRC cells with high level of CDK5(CDK5-high)displayed midzone mitochondrial division that was associated with oncogenic phenotype,but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells.Mechanistically,pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor(MFF)to mitochondrial fission 1 protein(FIS1).Thus,our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells,which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

Alteration of mitochondrial protein succinylation against cellular oxidative stress in cancer

Dear Editor,Lysine residue succinylation is a novel post-translational modification that recently attracted extensive attention.Succinylation is achieved by non-enzymatic processes or by a series of enzymes[like p300,lysine acetyltransferase 2A(KAT2A)]that transfer the succinyl groups from succinyl-coenzyme A(CoA)to the specific lysine,modulating protein function in various physiological processes[1].As a high-energy metabolite,succinyl-CoA is mainly produced within the mitochondrial matrix and peroxisomes.Its high-rate generation in the tricarboxylic acid(TCA)cycle and its impermeability across the mitochondrial inner membrane(due to its negative charge property)enhance succinyl-CoA accumulation within mitochondria.

Copy number variation of NAL23 causes narrow-leaf development in rice

Leaf shape is a key trait for plant architecture relating to photosynthesis and transpiration in plants(Lawson et al.,2020).Erect leaves with proper leaf length and width,particularly the upper three leaves in cereal crops,could significantly improve light absorption efficiency in canopy and ultimately increase crop yield(Jiao et al.,2010).Rice leaves initiate at the peripheral zone of shoot apical meristem,then develop along the proximal-distal,adaxial-abaxial,and mediallateral axes to form a flat symmetric architecture(Du et al.,2018).

GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed.Here,a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs.A series of functional assays showed that desloratadine,an antiallergic drug,can repress proliferation in HCC cell lines,cell-derived xenograft(CDX),patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.N-myristoyl transferase 1(NMT1)was identified as a target protein of desloratadine by drug affinity responsive target stability(DARTS)and surface plasmon resonance(SPR)assays.Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo.Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3(VILIP3)was a new substrate of NMT1 in protein N-myristoylation modification,and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC.Mechanistically,desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity,disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling.Conclusively,this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

MiR-16-5p plays an inhibitory role in human non-small cell lung cancer through Fermitin family member 2

Increasing evidence indicates that aberrant expressions of some microRNAs are associated with cancer progression.However,the roles and biological mechanisms of miRNA-16-5p in human non-small cell lung cancer(NSCLC)are not to be well studied.Here,we validated that the expression of miR-16-5p was decreased significantly in NSCLC samples and cell lines.The correlation between the clinicopathological features of NSCLC and the miR-16-5p expression showed that the expression of miR-16-5p in non-small cell lung cancer was linked with the advanced TNM stage,positive lymph node metastasis,with short overall survival(OS).Also,a negative correlation between miR-16-5p and Fermitin family member 2(FERMT2)was observed,implying there may be a potential link about their regulation.The hypothesis was further confirmed by in-silico analysis and dual-luciferase reporter assay.Moreover,we demonstrated that the transfections of miR-16-5p mimics could alter some biological characteristics of NSCLC cells remarkably accomplished by the expression variance of FERMT2 in vitro and in vivo assays.Summarily,this study demonstrated that miR-16-5p,as a tumor suppression factor in NSCLC by targeting FERMT2,could serve as one promising biomarker in the prediction for NSCLC patients.

Small-molecule agents for cancer immunotherapy

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner

As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol.By using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of penfluridol.Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of penfluridol.High PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor growth.Mechanistically,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner.Taken together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease.

Identification of miR-515-3p and its targets,vimentin and MMP3,as a key regulatory mechanism in esophageal cancer metastasis:functional and clinical significance

Metastasis is the main factor of treatment failure in cancer patients,but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed.This study aims to explore novel key metastasis-related microRNAs(miRNAs)in esophageal squamous cell carcinoma(ESCC).By comparing miRNA profiles of the highly metastatic ESCC cell sublines,we established through serial in vivo selection with the parental cells,we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues,further decreased in metastatic tumors,and moreover,markedly associated with advanced stage,metastasis and patient survival.The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers,and more importantly,suppress invasion and metastasis of ESCC cells.Mechanistically,we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3(MMP3)expression by binding to the coding sequence and 3′untranslated region,respectively.In addition,the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues,which may lead to deregulation of miR-515-3p expression in ESCC.Furthermore,our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice.Taken together,this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.

Promotion of cell proliferation and inhibition of ADCC by cancerous immunoglobulin expressed in cancer cell lines

To explore the significance of cancerous immunoglobulin(Ig)in cancer cell growth,HeLa cervical cancer cells were stably transfected with small interfering RNA(siRNA)that specifically,efficiently and consistently silences the expression of heavy chain genes of all immunoglobulin isotypes.This stable cell line was used to examine cell viability,colony formation and tumor growth in athymic nude mice.The results of these experiments indicated that siRNA-mediated knockdown of cancerous Ig inhibited cell growth in vitro and suppressed tumor cell growth in immune-deficient nude mice in vivo.Similarly,this siRNA also inhibited the growth of MGC gastric cancer cells and MCF-7 breast cancer cells.Furthermore,the presence of cancerous Ig specifically reduced antibody-dependent cell-mediated cytotoxicity(ADCC)induced by an anti-human epithelial growth factor receptor(EGFR)antibody in a dose-dependent manner,suggesting that the cancerous Ig-Fc receptor interaction inhibits natural killer cell(or NK cell)effector function.The prevalent expression of Ig in human carcinomas and its capacity to promote growth and inhibit immunity might have important implications in growth regulation and targeted therapy for human cancers.

Heterogeneity of aberrant immunoglobulin expression in cancer cells

Accumulating evidence has shown that immunoglobulin(Ig)is‘unexpectedly’expressed by epithelial cancer cells and that it can promote tumor growth.The main purpose of this study was to explore the components of the cancerous Ig and its possible function.The presence of cancerous Ig in the Golgi apparatus was confirmed by immunofluorescence,indirectly suggesting that the cancerous Ig was processed and packaged in cancer cells.Western blot analysis and ELISA results indicated that cancer cells produced membrane Ig and secreted Ig into the supernatant fraction.The cancerous Ig consists of an a heavy chain and a k light chain.Finally,by analyzing the Ig components pulled down by protein A beads,the cancerous Ig was found to be structurally distinct from normal Ig.The cancerous Ig was truncated or aberrant.Although the underlying mechanism that causes the abnormalities has not been determined,our current discoveries strengthen our previous findings and promise fruitful future explorations.

Activation of the Ig la I promoter by the transcription factor Ets-1 triggers Ig lal-Cal germline transcription in epithelial cancer cells

Immunoglobulins （Igs） are known to be synthesized and secreted only by B lymphocytes. Class switch recombination （CSR） is a key event that enables B cells to express Igs, and one of the crucial steps for CSR initiation is the germline transcription of Iggenes. Surprisingly, recent studies have demonstrated that the Iggenes are also expressed in some epithelial cancer cells; however, the mechanisms underlying how cancer cells initiate CSR and express Igs are still unknown. In this study, we confirmed that the Ig la I promoter in cancer cell lines was activated by the Ets- 1 transcription factor, and the activity of the Ig la I promoter and ig lal-C^l germiine transcription were attenuated after knockdown of Ets-1 by specific small interfering RNAs （siRNA）. Furthermore, the expression of Ets-1 and Iga heavy chain in cancer cells was dose dependently upregulated by TGF-I^I. These results indicate that activation of the Ig lal promoter by the transcriotion factor Ets-1 is a critical Dathwav and orovides a novel mechanism for le exoression in non-B cell cancers.

Genome-wide identification of key regulatory lncRNAs in esophageal cancer metastasis

Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systematic identification and functional validation of metastasis-associated long non-coding RNAs(lncRNAs)and microRNAs(miRNAs),as well as-their interactions in ESCC are urgently needed.

AID expression increased by TNF-α is associated with class switch recombination of Igα gene in cancers

Recently, immunoglobulins （Igs） were unexpectedly found to be expressed in epithelial cancers. Immunoglobulin class switching or class switch recombination （CSR） is a natural biological process that alters a B cell＇s production of antibodies （immunoglobulins） from one class to another. However, the mechanism of CSR of Iggenes in cancer is still unknown. Here, we confirmed by detecting the hallmark of CSR that the Iga gene in cancer underwent CSR. Then we focused on activation-induced cytidine deaminase （AID）, a crucial factor for initiating CSR. Further studies using tumor necrosis factor （TNF）-α stimulation and specific inhibitor of NF-KB revealed that TNF-α could increase AID expression through NF-κB signaling. Finally, we demonstrated that AID could co-localize with protein kinase A and bind to the switching （Sα） region of the Igα gene. Overexpression of AID obviously enhanced Igα heavy chain expression and its binding ability to the Sa region. These findings indicated that TNF-α-induced AID expression is involved with CSR in cancer.

ISGylation orchestrates the degradation flux of cellular cargo toward lysosome

Post-translational modification(PTM)is a critical step for nascent protein processing,which accompanies with proteins lifetime to modulate their functions dynamically.Currently,there are over 300 species of PTMs been identified,including chemical group modification(e.g.,phosphate,acetyl,methyl,or succinyl groups)and ubiquitin-like(UBL)group modification(e.g.,ubiquitination,SUMOylation,and ISGylation).

New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer

With the development of proteomics and epigenetics,a large number of RNA-binding proteins(RBPs)have been discovered in recent years,and the inter-action between long non-coding RNAs(lncRNAs)and RBPs has also received increasing attention.It is extremely important to conduct in-depth research on the lncRNA-RBP interaction network,especially in the context of its role in the occurrence and development of cancer.Increasing evidence has demonstrated that lncRNA-RBP interactions play a vital role in cancer progression;there-fore,targeting these interactions could provide new insights for cancer drug discovery.In this review,we discussed how lncRNAs can interact with RBPs to regulate their localization,modification,stability,and activity and discussed the effects of RBPs on the stability,transport,transcription,and localization of lncRNAs.Moreover,we explored the regulation and influence of these inter-actions on lncRNAs,RBPs,and downstream pathways that are related to can-cer development,such as N6-methyladenosine(m6A)modification of lncRNAs.In addition,we discussed how the lncRNA-RBP interaction network regulates cancer cell phenotypes,such as proliferation,apoptosis,metastasis,drug resis-tance,immunity,tumor environment,and metabolism.Furthermore,we sum-marized the therapeutic strategies that target the lncRNA-RBP interaction net-work.Although these treatments are still in the experimental stage and various theories and processes are still being studied,we believe that these strategiesmay provide new ideas for cancer treatment.

Advances in targeted therapy for esophageal cancer

Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in China.Currently,surgical resection,radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer.However,outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments.As a new type of approach,targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer;these include cetuximab and bevacizumab,which target epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF),respectively.In addition,other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed.For example,trastuzumab,a monoclonal antibody targeting human epidermal growth factor receptor 2(HER-2),has been approved by the Food and Drug Administration(FDA)as a first-line treatment of HER-2-positive cancer.Moreover,the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma(ESCC).These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients.Nevertheless,adverse events,optimal dosages and effective combinations still need further investigation.In this review,we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs,discuss their efficacy and safety,and provide a clinical rationale for precision medicine in esophageal cancer.

Understanding the proteome encoded by “non-coding RNAs”:new insights into human genome

A great number of non-coding RNAs(ncRNAs) account for the majority of the genome. The translation of these ncRNAs has been noted but seriously underestimated due to both technological and theoretical limitations. Based on the development of ribosome profiling(Ribo-seq), full length translating RNA analysis(RNC-seq) and mass spectrometry technology, more and more ncRNAs are being found to be translated in different organism, and some of them can produce functional peptides. While recently, not only individual new functional proteins, but also a new proteome have been experimentally discovered to be encoded by endogenous lncRNAs and circRNAs. These new proteins are of biological significance, suggesting the connection of the translation of ncRNAs to human physiology and diseases. Therefore, an in-depth and systematic understanding of the coding capabilities of ncRNAs is necessary for basic biology and medicine. In this review, we summarize the advances in the field of discovering this new proteome, i.e. "ncRNA-coded" proteins.

Immunoglobulin Expression and Its Biological Significance in Cancer Cells

It is generally believed that the expression of a gene is restricted ＂within the right place and at the right time＂. This principle has long been considered applicable as well to the expression of immunoglobulin （Ig） lymphocytes of B cell lineage. However, increasing evidence has shown Ig ＂paradoxically＂ expressed in malignant tumors of epithelial origin. We reviewed the recent progress in the study of cancer-derived Ig, and also discussed its mechanisms and possible functions, trying to arouse interest and attention to those working in the field of immunology and oncology.