2023年 · 第136卷第07期

Long non-coding RNAs (lncRNAs) reportedly function as important modulators of gene regulation and malignant processes in the development of human cancers. The lncRNA JPX is a novel molecular switch for X chromosome inactivation and differentially expressed JPX has exhibited certain clinical correlations in several cancers. Notably, JPX participates in cancer growth, metastasis, and chemoresistance, by acting as a competing endogenous RNA for microRNA, interacting with proteins, and regulating some specific signaling pathways. Moreover, JPX may serve as a potential biomarker and therapeutic target for the diagnosis, prognosis, and treatment of cancer. The present article summarizes our current understanding of the structure, expression, and function of JPX in malignant cancer processes and discusses its molecular mechanisms and potential applications in cancer biology and medicine.

Alternative splicing (AS) is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs (mRNAs), extremely improving the richness of transcriptome and proteome. Both mammal hosts and pathogens require AS to maintain their life activities, and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS. Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA (named cis-splicing). Parasites also use spliceosomes to splice, but this splicing can occur among different mRNAs (named trans-splicing). Bacteria and viruses directly hijack the host’s splicing machinery to accomplish this process. Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators (abundance, modification, distribution, movement speed, and conformation), which further radiate to alterations in the global splicing profiles. Genes with splicing changes are enriched in immune-, growth-, or metabolism-related pathways, highlighting approaches through which hosts crosstalk with pathogens. Based on these infection-specific regulators or AS events, several targeted agents have been developed to fight against pathogens. Here, we summarized recent findings in the field of infection-related splicing, including splicing mechanisms of pathogens and hosts, splicing regulation and aberrant AS events, as well as emerging targeted drugs. We aimed to systemically decode host–pathogen interactions from a perspective of splicing. We further discussed the current strategies of drug development, detection methods, analysis algorithms, and database construction, facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel and minimally invasive technology. Since the US Food and Drug Administration approved unilateral ventral intermediate nucleus-MRgFUS for medication-refractory essential tremor in 2016, studies on new indications, such as Parkinson’s disease (PD), psychiatric diseases, and brain tumors, have been on the rise, and MRgFUS has become a promising method to treat such neurological diseases. Currently, as the second most common degenerative disease, PD is a research hotspot in the field of MRgFUS. The actions of MRgFUS on the brain range from thermoablation, blood-brain barrier (BBB) opening, to neuromodulation. Intensity is a key determinant of ultrasound actions. Generally, high intensity can be used to precisely thermoablate brain targets, whereas low intensity can be used as molecular therapies to modulate neuronal activity and open the BBB in conjunction with injected microbubbles. Here, we aimed to summarize advances in the application of MRgFUS for the treatment of PD, with a focus on thermal ablation, BBB opening, and neuromodulation, in the hope of informing clinicians of current applications.

Many nutritional supplements and pharmacological agents have been reported to show preventive effects on colorectal adenoma and colorectal cancer (CRC). We performed a network meta-analysis to summarize such evidence and assess the efficacy and safety of these agents.

We searched PubMed, Embase, and the Cochrane Library for studies published in English until October 31, 2021 that fit our inclusion criteria. We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of candidate agents (low-dose aspirin [Asp], high-dose Asp, cyclooxygenase-2 inhibitors [coxibs], calcium, vitamin D, folic acid, ursodeoxycholic acid [UDCA], estrogen, and progesterone, alone or in combination) for preventing colorectal adenoma and CRC. Cochrane risk-of-bias assessment tool was employed to evaluate the quality of each included study.

Thirty-two randomized controlled trials (278,694 participants) comparing 13 different interventions were included. Coxibs significantly reduced the risk of colorectal adenoma (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.44–0.79, six trials involving 5486 participants), advanced adenoma (RR: 0.63, 95% CI: 0.43–0.92, four trials involving 4723 participants), and metachronous adenoma (RR: 0.58, 95% CI: 0.43–0.79, five trials involving 5258 participants) compared with placebo. Coxibs also significantly increased the risk of severe adverse events (RR: 1.29, 95% CI: 1.13–1.47, six trials involving 7109 participants). Other interventions, including Asp, folic acid, UDCA, vitamin D, and calcium, did not reduce the risk of colorectal adenoma in the general and high-risk populations compared with placebo.

Considering the balance between benefits and harms, regular use of coxibs for prevention of colorectal adenoma was not supported by the current evidence. Benefit of low-dose Asp for chemoprevention of colorectal adenoma still requires further evidence.

PROSPERO, No. CRD42022296376

The hepatitis B virus (HBV) vaccine has been efficiently used for decades. However, hepatocellular carcinoma caused by HBV is still prevalent globally. We previously reported that interferon (IFN)-induced tripartite motif-containing 25 (TRIM25) inhibited HBV replication by increasing the IFN expression, and this study aimed to further clarify the anti-HBV mechanism of TRIM25.

The TRIM25-mediated degradation of hepatitis B virus X (HBx) protein was determined by detecting the expression of HBx in TRIM25-overexpressed or knocked-out HepG2 or HepG2-NTCP cells via Western blotting. Co-immunoprecipitation was performed to confirm the interaction between TRIM25 and HBx, and colocalization of TRIM25 and HBx was identified via immunofluorescence; HBV e-antigen and HBV surface antigen were qualified by using an enzyme-linked immunosorbent assay (ELISA) kit from Kehua Biotech. TRIM25 mRNA, pregenomic RNA (pgRNA), and HBV DNA were detected by quantitative real-time polymerase chain reaction. The retinoic acid-inducible gene I (RIG-I) and pgRNA interaction was verified by RNA-binding protein immunoprecipitation assay.

We found that TRIM25 promoted HBx degradation, and confirmed that TRIM25 could enhance the K90-site ubiquitination of HBx as well as promote HBx degradation by the proteasome pathway. Interestingly, apart from the Really Interesting New Gene (RING) domain, the SPRY domain of TRIM25 was also indispensable for HBx degradation. In addition, we found that the expression of TRIM25 increased the recognition of HBV pgRNA by interacting with RIG-I, which further increased the IFN production, and SPRY, but not the RING domain is critical in this process.

The study found that TRIM25 interacted with HBx and promoted HBx-K90-site ubiquitination, which led to HBx degradation. On the other hand, TRIM25 may function as an adaptor, which enhanced the recognition of pgRNA by RIG-I, thereby further promoting IFN production. Our study can contribute to a better understanding of host-virus interaction.

Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV).

We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development.

We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (<-2 standard deviations [SDs]), and 14 had significantly increased WBDV (>+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs. 75.0% [30/40], P= 0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes (P = 1.656e^-9). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron.

Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.

Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted.

We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored.

Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2–5] loci vs. 5 [3–5] loci, P = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P = 0.024). On the other hand, those with decreased CD4⁺/CD8⁺ T-cell ratio developed more fever (0.8 [0.7–1.2] vs. 1.4 [1.1–2.2], P = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932–0.995, P = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859–0.975, P = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control.

Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.

Antenatal corticosteroids (ACS) can significantly improve the outcomes of preterm infants. This study aimed to describe the ACS use rates among preterm infants admitted to Chinese neonatal intensive care units (NICU) and to explore perinatal factors associated with ACS use, using the largest contemporary cohort of very preterm infants in China.

This cross-sectional study enrolled all infants born at 24⁺⁰ to 31⁺⁶ weeks and admitted to 57 NICUs of the Chinese Neonatal Network from January 1st, 2019 to December 30th, 2019. The ACS administration was defined as at least one dose of dexamethasone and betamethasone given before delivery. Multiple logistic regressions were applied to determine the association between perinatal factors and ACS usage.

A total of 7828 infants were enrolled, among which 6103 (78.0%) infants received ACS. ACS use rates increased with increasing gestational age (GA), from 177/259 (68.3%) at 24 to 25 weeks’ gestation to 3120/3960 (78.8%) at 30 to 31 weeks’ gestation. Among infants exposed to ACS, 2999 of 6103 (49.1%) infants received a single complete course, and 33.4% (2039/6103) infants received a partial course. ACS use rates varied from 30.2% to 100% among different hospitals. Multivariate regression showed that increasing GA, born in hospital (inborn), increasing maternal age, maternal hypertension and premature rupture of membranes were associated with higher likelihood to receive ACS.

The use rate of ACS remained low for infants at 24 to 31 weeks’ gestation admitted to Chinese NICUs, with fewer infants receiving a complete course. The use rates varied significantly among different hospitals. Efforts are urgently needed to propose improvement measures and thus improve the usage of ACS.

The effect of intra-operative chemotherapy (IOC) on the long-term survival of patients with colorectal cancer (CRC) remains unclear. In this study, we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection.

1820 patients were recruited, and 1263 received IOC and 557 did not. Clinical and demographic data were collected, including overall survival (OS), clinicopathological features, and treatment strategies. Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models. A regression model was developed to analyze the independent effects of IOC.

Proportional hazard regression analysis showed that IOC (hazard ratio [HR]=0.53, 95% confidence intervals [CI] [0.43, 0.65], P < 0.001) was a protective factor for the survival of patients. The mean overall survival time in IOC group was 82.50 (95% CI [80.52, 84.49]) months, and 71.21 (95% CI [67.92, 74.50]) months in non-IOC group. The OS in IOC-treated patients were significantly higher than non-IOC-treated patients (P < 0.001, log-rank test). Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model (HR=0.53, 95% CI [0.43, 0.65], P < 0.001), model 2 (adjusted for age and gender, HR=0.52, 95% CI [0.43, 0.64], P < 0.001), and model 3 (adjusted for all factors, 95% CI 0.71 [0.55, 0.90], P = 0.006). The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II (HR = 0.46, 95% CI [0.31, 0.67]) or III disease (HR=0.59, 95% CI [0.45, 0.76]), regardless of pre-operative radiotherapy (HR=0.55, 95% CI [0.45, 0.68]) or pre-operative chemotherapy (HR=0.54, 95% CI [0.44, 0.66]).

IOC is an independent factor that influences the survival of CRC patients. It improved the OS of patients with stages II and III CRC after radical surgery.

chictr.org.cn, ChiCTR 2100043775.

Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases, while the causal effects of cholecystectomy on colorectal cancer (CRC) and other complications are still unknown.

We obtained genetic variants associated with cholecystectomy at a genome-wide significant level (P value <5 × 10^-8) as instrumental variables (IVs) and performed Mendelian randomization (MR) to identify the complications of cholecystectomy. Furthermore, the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy, and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis. The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines.

The selected IVs explained 1.76% variance of cholecystectomy. Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC (odds ratio [OR] =1.543, 95% confidence interval [CI]: 0.607–3.924). Also, it was not significant in either colon or rectum cancer. Intriguingly, cholecystectomy might decrease the risk of Crohn’s disease (OR = 0.078, 95% CI: 0.016-0.368) and coronary heart disease (OR = 0.352, 95% CI: 0.164–0.756). However, it might increase the risk of irritable bowel syndrome (IBS) (OR = 7.573, 95% CI: 1.096–52.318). Cholelithiasis could increase the risk of CRC in the largest population (OR = 1.041, 95% CI: 1.010–1.073). The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population (OR = 1.061, 95% CI: 1.002–1.125) after adjustment of cholecystectomy.

The study indicated that cholecystectomy might not increase the risk of CRC, but such a conclusion needs further proving by clinical equivalence. Additionally, it might increase the risk of IBS, which should be paid attention to in clinical practice.

To the Editor: In recent years, impressive outcomes have been achieved in patients harboring human epidermal growth factor receptor 2 (HER2) mutations, which accounts for 1% to 4% of cases in non-small cell lung cancer (NSCLC).^[1]Previously, we observed that pyrotinib showed potent efficacy inHER2exon 20 YVMA insertion NSCLC patient-derived organoids and patient-derived xenograft models,^[2]and confirmed its efficacy in a phase II clinical trial with an objective response rate (ORR) of 30.0% and a median progression-free survival (PFS) of 6.9 months in the later-line setting,^[3]suggesting the potential of pyrotinib to serve as a novel standard of care (SoC) in the later-line setting. Currently, single agent chemotherapy or immune checkpoint inhibitors (ICIs) are the SoC for the later-line treatment of advanced NSCLC, and recent studies have found that the combination of chemo-immunotherapy treatment shows superior efficacy.^[4]To compare the efficacy of pyrotinib with current SoC in the second- or third-line settings, we retrospectively collected data of 182 patients from Tongji University School of Medicine Cancer Institute and reported the outcomes here.

To the Editor:Anaplastic lymphoma kinase (ALK) fusion oncogene occurs in 3% to 7% of patients with non-small cell lung cancer (NSCLC), with the most common companion being echinoderm microtubule-associated protein-like 4.^[1]Ceritinib is an oral, small-molecule, adenosine triphosphate (ATP)-competitive drug, and tyrosine kinase inhibitor of ALK (ALK-TKI) that is 20 times more potent than crizotinib in enzymological tests.^[2]To date, there are few prospective clinical trials of neoadjuvant targeted therapy in patients with ALK-positive locally advanced NSCLC. Therefore, the value of ceritinib in ALK-positive stage IIIA (N2) NSCLC is unknown. In this study, we reported the efficiency of ceritinib used as initial neoadjuvant targeted therapy in patients with ALK-positive IIIA (N2) NSCLC.

To the Editor:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for hematologic disease. High-intensity preconditioning in allo-HSCT patients significantly increases the risk of severe infection, which is an important cause of early transplant-related death. Granulocyte-colony stimulating factor (G-CSF) infusion can promote hematopoiesis, accelerate reconstruction of the immune system, reduce the duration of febrile neutropenia (FN), and decrease the incidence of infections. In addition, the increased risk of infection is thought to be partly due to hypogammaglobulinemia after HSCT. Therefore, some centers argue that prophylactic administration of intravenous immunoglobulin (IVIG) after HSCT is the standard of care.

To the Editor: Preeclampsia presents with new-onset hypertension and maternal multi-organ injury that is associated with substantial maternal and fetal morbidity and mortality.^[1]Although the etiology remains a mystery, environmental toxicants, especially those that interact with genetic factors and disrupt normal placental function, are emerging as potential risk factors for preeclampsia. Perfluoroalkyl and polyfluoroalkyl substances (PFAS), a kind of aliphatic chemicals, have been widely used in industries and consumer products for their excellent properties of heat-, water- and oil-resistance, leading to ubiquitous contamination and inevitable human exposure. The long-chain perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), as the most widely used representatives, have been detected in the blood, human cord blood, and breast milk of the general population.^[2]Previously, several epidemiological studies have examined the associations between PFOS/PFOA and preeclampsia, but have found inconsistent results, which may reflect differences in outcome assessments, analysis methods, and/or study population.^[3]Since the 3M Company, one of the largest PFAS manufacturers, phased out PFOS and PFOA production from 2002, PFOS and PFOA production volumes have been increasing in China. However, the risk of preeclampsia with PFOS and PFOA exposure is much rarely described in China, especially in the most intensively industrialized regions, such as the eastern coast. Thus, we explore the association between maternal serum concentrations of PFOS and PFOA and the risk of developing preeclampsia in Shanghai, China.

To the Editor: Transmembrane serine protease 4 (TMPRSS4; OMIM: 606565), which encodes a member of the serine protease family, is involved in various biological processes related to diseases such as cancer and pediatric neurodegenerative disorders.^[1,2]Overexpression of this gene (NM_019894.4) was first identified in pancreatic carcinoma with metastasis and invasion,^[3]suggesting its potential as a therapeutic target and prognostic marker.^[4]Besides, TMPRSS4 has been found to promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into host cells by cleaving SARS-CoV-2 spike glycoproteins (S protein) into an active glycoprotein that facilitates coronavirus infection.^[5]

To the Editor: Oncology precision medicine aims to identify patients most likely to respond effectively to therapies. Efforts to establish a survival prediction model using a single platform have not yet met the precision medicine goals.^[1]Circulating tumor DNA (ctDNA), assessed by liquid biopsy, is representative of tumor heterogeneity, and ctDNA levels hold the potential for monitoring treatment response.^[2]Moreover, circulating tumor cells (CTCs) in the metastatic cascade have been identified as clinical factors associated with poor prognosis.^[3]The added value obtained from multi-omics fusion analysis to improve predictive models requires further investigation.^[4]

To the Editor: Myocardial ischemia/reperfusion injury (MI/RI) often causes death, dysfunction, or damage to the cardiomyocytes, and thus more effective clinical treatments are required.^[1]MicroRNAs (miRNAs) bind to target mRNAs to regulate post-transcriptional gene expression, with important effects on MI/RI by regulating critical molecular signaling pathways.^[2]Previous studies have shown that flavonoids have beneficial effects on cardiac function and the outcomes after cardiac operations. Luteolin is a type of flavonoid, and high dietary intake of luteolin-rich food decreases the myocardial infarction area.^[3]However, the transcriptional mechanism that allows luteolin to modulate gene expression and protect against MI/RI remains unknown. In this study, we screened the miRNAs with the greatest effects in MI/RI models after luteolin pretreatment. We identified the target gene of the miRNAs and explored the mechanisms associated with the protective effects of luteolin against MI/RI bothin vitroandin vivo. All the experiments were performed in accordance with guidelines and approved by the Animal Ethics Committee of the Xuzhou Medical University (No. CMCACUC2014-04-027).

To the Editor: Cardiac resynchronization therapy (CRT) is an effective treatment for advanced chronic heart failure (HF) patients with reduced ejection fraction. Despite its beneficial effects on cardiac function, traditional biventricular epicardial pacing (BiVP-epi) could not reduce ventricular arrhythmias (VAs) burden in all HF patients.^[1]The increase in the dispersion of ventricular repolarization (DVR) after BiVP-epi in non-responders may play a role.^[2]Recently, left bundle branch area pacing (LBBAP) has been reported as a feasible option for CRT delivery, while little is known about its influence on DVR. This retrospective study aimed to thoroughly evaluate the changes of DVR after LBBAP in HF patients and compare the repolarization features between LBBAP and BiVP-epi.

To the Editor: In China, depression is a common mental illness with a lifetime prevalence of 6.8% and a 12-month prevalence of 3.6%.^[1]The study aimed to determine the prevalence of depression and its relationship with associated lifestyle factors in Chinese adults aged 18 years and over using a large-scale, cross-sectional survey.

To the Editor:Chronic kidney disease (CKD) is a global burden of the public health. The global prevalence of CKD exceeded 10% while the awareness was around 10%.^[1]In the era of big data, improving the identification of CKD using informatic tools is important. Computable phenotype is proven as an efficient tool to facilitate the process of patient identification using electronic health record (EHR) data. It is an automatic algorithm identifying the target population through objective criteria with logic statements. Effective implementation of a computable phenotype depends on valid mapping of raw data to a standard set of data and definitions. Previous studies developed computable phenotypes for CKD identification in English by using the Logical Observation Identifiers Names and Codes (LOINC) and the International Classification of Diseases (ICD) codes.^[2,3]With the limited utilization of these codes and the language barrier, implementing these computable phenotypes in non-English circumstances and/or in the absence of identical coding system is difficult.