Volume 136 · Issue 07 · 2023

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.

致编辑近年来，在携带人表皮生长因子受体2的患者中取得了令人印象深刻的结果（HER2)突变，在非小细胞肺癌(NSCLC)中占1%至4%的病例。^[1]先前，我们观察到吡咯替尼在以下方面显示出有效的疗效HER2外显子20 YVMA插入NSCLC患者来源的类器官和患者来源的异种移植模型，^[2]并在II期临床试验中以30.0%的客观缓解率（ORR）和6.9个月的后期线设置中位无进展生存期（PFS）证实了其疗效，^[3]表明吡咯替尼有可能在后期治疗中作为一种新的标准治疗（SoC）。目前，单药化疗或免疫检查点抑制剂（ICIs）是晚期非小细胞肺癌后期治疗的SoC，近期研究发现化疗-免疫联合治疗显示出优越的疗效。^[4]为了比较吡咯替尼与当前SoC在二线或三线环境中的疗效，我们回顾性收集了同济大学医学院肿瘤研究所182例患者的数据，并在此报告结果。

致编辑：间变性淋巴瘤激酶（ALK）融合癌基因发生在3%~7%的非小细胞肺癌（NSCLC）患者中，最常见的伴随物是棘皮动物微管相关蛋白样4。^[1]Ceritinib是一种口服、小分子、三磷酸腺苷（ATP）竞争性药物，是ALK酪氨酸激酶抑制剂（ALK-TKI），在酶学测试中的效力是克唑替尼的20倍。^[2]迄今为止，ALK阳性局部晚期非小细胞肺癌患者新辅助靶向治疗的前瞻性临床试验很少。因此，色瑞替尼在ALK阳性IIIA（N2）期非小细胞肺癌中的价值尚不清楚。在这项研究中，我们报告了塞瑞替尼作为初始新辅助靶向治疗在ALK阳性IIIA（N2）非小细胞肺癌患者中的疗效。

致编辑：异基因造血干细胞移植（allo-HSCT）是治疗血液病的重要手段。allo-HSCT患者的高强度预处理显著增加了严重感染的风险，这是早期移植相关死亡的重要原因。粒细胞集落刺激因子（G-CSF）输注可促进造血，加速免疫系统重建，缩短发热性中性粒细胞减少症（FN）的持续时间，降低感染的发生率。此外，感染风险的增加被认为部分是由于HSCT后的低丙种球蛋白血症。因此，一些中心认为HSCT后预防性给予静脉免疫球蛋白（IVIG）是护理的标准。

致编辑：先兆子痫表现为新发高血压和母体多器官损伤，与大量母体和胎儿发病率和死亡率相关。^[1]尽管病因仍然是个谜，但环境毒物，尤其是那些与遗传因素相互作用并破坏正常胎盘功能的毒物，正在成为先兆子痫的潜在危险因素。全氟烷基和多氟烷基物质（PFAS）是一种脂肪族化学品，因其优异的耐热、耐水、耐油性能而广泛应用于工业和消费品中，导致无处不在的污染和不可避免的人类接触。长链全氟辛烷磺酸（PFOS）和全氟辛酸（PFOA）作为使用最广泛的代表，已在普通人群的血液、人脐带血和母乳中检测到。^[2]此前，几项流行病学研究检查了全氟辛烷磺酸/全氟辛烷磺酸与先兆子痫之间的联系，但发现了不一致的结果，这可能反映了结果评估、分析方法和/或研究人群的差异。^[3]自2002年最大的PFAS生产商之一3M公司逐步淘汰PFOS和PFOA生产以来，中国的PFOS和PFOA产量一直在增加。然而，在中国，特别是在工业化最密集的地区，如东海岸，全氟辛烷磺酸和全氟辛烷磺酸暴露导致先兆子痫的风险很少被描述。因此，我们在中国上海探讨了全氟辛烷磺酸和全氟辛烷磺酸母体血清浓度与先兆子痫风险之间的关系。

致编辑：跨膜丝氨酸蛋白酶4（TMPRSS4;OMIM：606565)，其编码丝氨酸蛋白酶家族的成员，参与与疾病如癌症和儿科神经变性病症相关的各种生物学过程。^[1,2]该基因（NM_019894.4）的过表达首次在有转移和侵袭的胰腺癌中被发现，^[3]提示其作为治疗靶点和预后标志物的潜力。^[4]此外，已经发现TMPRSS4通过将新型冠状病毒刺突糖蛋白（S蛋白）切割成促进冠状病毒感染的活性糖蛋白来促进严重急性呼吸综合征冠状病毒2（新型冠状病毒）进入宿主细胞。^[5]

致编辑：肿瘤精准医疗旨在识别最有可能对疗法产生有效反应的患者。使用单一平台建立生存预测模型的努力尚未达到精准医疗目标。^[1]通过液体活检评估的循环肿瘤DNA（ctDNA）代表肿瘤异质性，并且ctDNA水平具有监测治疗反应的潜力。^[2]此外，转移级联中的循环肿瘤细胞(CTC)已被鉴定为与不良预后相关的临床因素。^[3]从多组学融合分析中获得的改进预测模型的附加值需要进一步研究。^[4]

致编辑：心肌缺血/再灌注损伤（MI/RI）通常导致心肌细胞死亡、功能障碍或损伤，因此需要更有效的临床治疗。^[1]微小RNA（miRNAs）与靶mRNA结合以调节转录后基因表达，通过调节关键分子信号通路对MI/RI具有重要影响。^[2]先前的研究表明，类黄酮对心脏功能和心脏手术后的结果有有益的影响。木犀草素是黄酮类化合物的一种，饮食中大量摄入富含木犀草素的食物可减少心肌梗死面积。^[3]然而，允许木犀草素调节基因表达和防止MI/RI的转录机制仍然未知。在这项研究中，我们筛选了木犀草素预处理后在MI/RI模型中影响最大的miRNA。我们鉴定了miRNAs的靶基因，并探讨了木犀草素对MI/RI的保护作用机制体外和体内所有实验均按照指南进行，并经徐州医科大学动物伦理委员会批准（编号CMCACUC2014-04-027）。

致编辑：心脏再同步治疗（CRT）是射血分数降低的晚期慢性心力衰竭（HF）患者的有效治疗方法。尽管传统的双心室心外膜起搏（BiVP-epi）对心功能有益，但不能减少所有心力衰竭患者的室性心律失常（VAs）负担。^[1]无应答者BiVP-epi后心室复极离散度（DVR）的增加可能起作用。^[2]最近，左束支区起搏（LBBAP）被报道为CRT输送的可行选择，而对其对DVR的影响知之甚少。本回顾性研究旨在全面评估HF患者LBBAP后DVR的变化，并比较LBBAP和BiVP-epi的复极特征。

致编辑：在中国，抑郁症是一种常见的精神疾病，终生患病率为6.8%，12个月患病率为3.6%。^[1]本研究旨在通过大规模横断面调查，确定18岁及以上中国成年人的抑郁症患病率及其与相关生活方式因素的关系。

致编辑：慢性肾脏病（CKD）是全球性的公共卫生负担。CKD的全球患病率超过10%，而知晓率约为10%。^[1]在大数据时代，使用信息工具改善CKD的识别非常重要。可计算表型被证明是一种有效的工具，可以促进使用电子健康记录（EHR）数据的患者识别过程。它是一种自动算法，通过带有逻辑语句的客观标准来识别目标人群。可计算表型的有效实现取决于原始数据到一组标准数据和定义的有效映射。先前的研究通过使用逻辑观察标识符名称和代码（LOINC）和国际疾病分类（ICD）代码开发了用于英语CKD识别的可计算表型。^[2,3]由于这些编码的有限利用和语言障碍，在非英语环境和/或缺乏相同编码系统的情况下实现这些可计算的表型是困难的。