Inter3D: Capture of TAD Reorganization Endows Variant Patterns of Gene Transcription.

Topologically associating domain (TAD) reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs. However, functional genes impacted by TAD alteration and the underlying mechanism of TAD reorganization regulating gene transcription remain to be fully elucidated. Here, we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization. Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B (MYL12B) locus, via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells, thereby exhibiting a significant correlation with the down-regulation of its transcriptional activity. Conversely, the fusion of TADs facilitated intrachromosomal interactions, suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1 (CYP27B1). Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription. The Inter3D pipeline developed in this study is freely available at https://github.com/bm2-lab/inter3D and https://ngdc.cncb.ac.cn/biocode/tool/BT7399.

Clinical Effectiveness of Automated Coronary CT-derived Fractional Flow Reserve: A Chinese Randomized Controlled Trial.

Background Coronary CT-derived fractional flow reserve (CT-FFR) has been used in patients with suspected coronary artery disease (CAD); however, whether it decreases invasive coronary angiography (ICA) use and affects prognosis remains insufficiently evidenced. Purpose To explore the effectiveness of adding CT-FFR to routine coronary CT angiography (CCTA) on short-term ICA rate and major adverse cardiovascular events (MACE) in a Chinese setting. Materials and Methods A multicenter randomized controlled trial was conducted in 17 Chinese centers, with patient inclusion from May 2021 to September 2021. Eligible individuals with 25%-99% stenosis at CCTA were randomly assigned 1:1 to a strategy of CCTA plus automated CT-FFR or CCTA alone for guiding downstream care. The primary end point was the ICA rate 90 days after enrollment. Secondary end points included 90-day and 1-year MACE rates (comprised of all-cause mortality, nonfatal myocardial infarction, and urgent revascularization) and 1-year cardiac events (comprised of cardiac death, nonfatal myocardial infarction, and urgent revascularization). The Cox proportional hazards model with center effect adjustment was used for survival comparisons. Results A total of 5297 participants (mean age, 63.5 years ± 10.8 [SD]; 3178 male) were included. During the 90-day follow-up, ICA was performed in 263 of 2633 participants (10.0%) in the CCTA plus CT-FFR group and 327 of 2640 participants (12.4%) in the CCTA-alone group (absolute rate difference: -2.40%; 95% CI: -4.10, -0.70; P = .006). The MACE rates at 90 days (0.5% [12 of 2633 participants] vs 0.8% [21 of 2640 participants]; P = .12) and 1 year (2.9% [74 of 2546 participants] vs 2.8% [72 of 2531 participants]; P = .90) were similar for both groups. At 1-year follow-up, fewer cardiac events were observed in the CCTA plus CT-FFR group compared with the CCTA-alone group (0.5% vs 1.1%; adjusted hazard ratio: 0.52; 95% CI: 0.27, 0.99; P = .047). Conclusion CT-FFR added to CCTA led to a lower 90-day ICA rate and similar 1-year MACE rate in a Chinese real-world setting. Further follow-up is warranted to demonstrate the long-term prognostic value of this management approach. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Pundziute-do Prado in this issue.

Peptidylprolyl isomerase A guides SENP5/GAU1 DNA-lncRNA triplex generation for driving tumorigenesis.

The three-stranded DNA-RNA triplex hybridization is involved in various biological processes, including gene expression regulation, DNA repair, and chromosomal stability. However, the DNA-RNA triplex mediating mechanisms underlying tumorigenesis remain to be fully elucidated. Here, we show that peptidylprolyl isomerase A (PPIA) serves as anchor to recruit GAU1 lncRNA by interacting with exon 4 of GAU1 and enhances the formation of SENP5/GAU1 DNA-lncRNA triplex. Intriguingly, TFR4 region of GAU1 exon 3 and TTS4 region of SENP5 promoter DNA constitute fragments forming the SENP5/GAU1 triplex. The SENP5/GAU1 triplex subsequently triggers the recruitment of the methyltransferase SET1A to exon 1 of GAU1, leading to the enrichment of H3K4 trimethylation and the activation of SENP5 transcription for driving the tumorigenesis of gastric cancer in vitro and in vivo. Our study reveals a mechanism of PPIA-guided SENP5/GAU1 DNA-lncRNA triplex formation in tumorigenesis and providing a concept in the dynamics of isomerase assisted DNA-RNA hybridization.

Preoperative predictive model for the probability of lymph node metastasis in gastric cancer: a retrospective study.

Background: Effectively diagnosing lymph node (LN) metastasis (LNM) is crucial in determining the condition of patients with gastric cancer (GC). The present study was devised to develop and validate a preoperative predictive model (PPM) capable of assessing the LNM status of individuals with GC. Methods: A retrospective analysis of consecutive GC patients from two centers was conducted over the period from January 2021 to December 2023. These patients were utilized to construct a 289-patient training cohort for identifying LNM-related risk factors and developing a PPM, as well as a 90-patient testing cohort used for PPM validation. Results: Of the GC patients included in the training cohort, 67 (23.2%) and 222 (76.8%) were respectively LNM negative and positive. Risk factors independently related to LNM status included cT3 invasion (P = 0.001), CT-reported LN (+) (P = 0.044), and CA199 value (P = 0.030). LNM risk scores were established with the following formula: score = -2.382 + 0.694×CT-reported LN status (+: 1; -: 0)+2.497×invasion depth (cT1: 0; cT2: 1; cT3: 2)+0.032×CA199 value. The area under the curve (AUC) values for PPM and CT-reported LN status were 0.753 and 0.609, respectively, with a significant difference between them (P < 0.001). When clinical data from the testing cohort was included in the PPM, the AUC values for the PPM and CT-reported LN status were 0.756 and 0.568 (P < 0.001). Conclusions: The established PPM may be an effective technique for predicting the LNM status of patients preoperatively. This model can better diagnose LNM than CT-reported LN status alone, this model is better able to diagnose LNM.

Prohibitin 2 orchestrates long noncoding RNA and gene transcription to accelerate tumorigenesis.

The spatial co-presence of aberrant long non-coding RNAs (lncRNAs) and abnormal coding genes contributes to malignancy development in various tumors. However, precise coordinated mechanisms underlying this phenomenon in tumorigenesis remains incompletely understood. Here, we show that Prohibitin 2 (PHB2) orchestrates the transcription of an oncogenic CASC15-New-Isoform 2 (CANT2) lncRNA and the coding tumor-suppressor gene CCBE1, thereby accelerating melanoma tumorigenesis. In melanoma cells, PHB2 initially accesses the open chromatin sites at the CANT2 promoter, recruiting MLL2 to augment H3K4 trimethylation and activate CANT2 transcription. Intriguingly, PHB2 further binds the activated CANT2 transcript, targeting the promoter of the tumor-suppressor gene CCBE1. This interaction recruits histone deacetylase HDAC1 to decrease H3K27 acetylation at the CCBE1 promoter and inhibit its transcription, significantly promoting tumor cell growth and metastasis both in vitro and in vivo. Our study elucidates a PHB2-mediated mechanism that orchestrates the aberrant transcription of lncRNAs and coding genes, providing an intriguing epigenetic regulatory model in tumorigenesis.

Corrigendum to 'Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma' (JHEP Reports 5 [2023] 100806).

[This corrects the article DOI: 10.1016/j.jhepr.2023.100806.].

Can Machine Learning Models Based on Computed Tomography Radiomics and Clinical Characteristics Provide Diagnostic Value for Epstein-Barr Virus-Associated Gastric Cancer?

OBJECTIVE: The aim of this study was to explore whether machine learning model based on computed tomography (CT) radiomics and clinical characteristics can differentiate Epstein-Barr virus-associated gastric cancer (EBVaGC) from non-EBVaGC. METHODS: Contrast-enhanced CT images were collected from 158 patients with GC (46 EBV-positive, 112 EBV-negative) between April 2018 and February 2023. Radiomics features were extracted from the volumes of interest. A radiomics signature was built based on radiomics features by the least absolute shrinkage and selection operator logistic regression algorithm. Multivariate analyses were used to identify significant clinicoradiological variables. We developed 6 ML models for EBVaGC, including logistic regression, Extreme Gradient Boosting, random forest (RF), support vector machine, Gaussian Naive Bayes, and K-nearest neighbor algorithm. The area under the receiver operating characteristic curve (AUC), the area under the precision-recall curves (AP), calibration plots, and decision curve analysis were applied to assess the effectiveness of each model. RESULTS: Six ML models achieved AUC of 0.706-0.854 and AP of 0.480-0.793 for predicting EBV status in GC. With an AUC of 0.854 and an AP of 0.793, the RF model performed the best. The forest plot of the AUC score revealed that the RF model had the most stable performance, with a standard deviation of 0.003 for AUC score. RF also performed well in the testing dataset, with an AUC of 0.832 (95% confidence interval: 0.679-0.951), accuracy of 0.833, sensitivity of 0.857, and specificity of 0.824, respectively. CONCLUSIONS: The RF model based on clinical variables and Rad_score can serve as a noninvasive tool to evaluate the EBV status of gastric cancer.

Non-malignant pathological results from CT-guided biopsy for pulmonary nodules: a predictive model for identifying false-negative results.

BACKGROUND: Computed tomography (CT)-guided biopsy (CTB) procedures are commonly used to aid in the diagnosis of pulmonary nodules (PNs). When CTB findings indicate a non-malignant lesion, it is critical to correctly determine false-negative results. Therefore, the current study was designed to construct a predictive model for predicting false-negative cases among patients receiving CTB for PNs who receive non-malignant results. MATERIALS AND METHODS: From January 2016 to December 2020, consecutive patients from two centers who received CTB-based non-malignant pathology results while undergoing evaluation for PNs were examined retrospectively. A training cohort was used to discover characteristics that predicted false negative results, allowing the development of a predictive model. The remaining patients were used to establish a testing cohort that served to validate predictive model accuracy. RESULTS: The training cohort included 102 patients with PNs who showed non-malignant pathology results based on CTB. Each patient underwent CTB for a single nodule. Among these patients, 85 and 17 patients, respectively, showed true negative and false negative PNs. Through univariate and multivariate analyses, higher standardized maximum uptake values (SUVmax, P = 0.001) and CTB-based findings of suspected malignant cells (P = 0.043) were identified as being predictive of false negative results. Following that, these two predictors were combined to produce a predictive model. The model achieved an area under the receiver operating characteristic curve (AUC) of 0.945. Furthermore, it demonstrated sensitivity and specificity values of 88.2% and 87.1% respectively. The testing cohort included 62 patients, each of whom had a single PN. When the developed model was used to evaluate this testing cohort, this yielded an AUC value of 0.851. CONCLUSIONS: In patients with PNs, the predictive model developed herein demonstrated good diagnostic effectiveness for identifying false-negative CTB-based non-malignant pathology data.

Induced dual-target rebalance simultaneously enhances efficient therapeutical efficacy in tumors.

Multiple gene abnormalities are major drivers of tumorigenesis. NF-κB p65 overactivation and cGAS silencing are important triggers and genetic defects that accelerate tumorigenesis. However, the simultaneous correction of NF-κB p65 and cGAS abnormalities remains to be further explored. Here, we propose a novel Induced Dual-Target Rebalance (IDTR) strategy for simultaneously correcting defects in cGAS and NF-κB p65. By using our IDTR approach, we showed for the first time that oncolytic adenovirus H101 could reactivate silenced cGAS, while silencing GAU1 long noncoding RNA (lncRNA) inhibited NF-κB p65 overactivation, resulting in efficient in vitro and in vivo antitumor efficacy in colorectal tumors. Intriguingly, we further demonstrated that oncolytic adenoviruses reactivated cGAS by promoting H3K4 trimethylation of the cGAS promoter. In addition, silencing GAU1 using antisense oligonucleotides significantly reduced H3K27 acetylation at the NF-κB p65 promoter and inhibited NF-κB p65 transcription. Our study revealed an aberrant therapeutic mechanism underlying two tumor defects, cGAS and NF-κB p65, and provided an alternative IDTR approach based on oncolytic adenovirus and antisense oligonucleotides for efficient therapeutic efficacy in tumors.

18F-FDG PET/CT based model for predicting malignancy in pulmonary nodules: a meta-analysis.

BACKGROUND: Several studies to date have reported on the development of positron emission tomography (PET)/computed tomography (CT)-based models intended to effectively distinguish between benign and malignant pulmonary nodules (PNs). This meta-analysis was designed with the goal of clarifying the utility of these PET/CT-based conventional parameter models as diagnostic tools in the context of the differential diagnosis of PNs. METHODS: Relevant studies published through September 2023 were identified by searching the Web of Science, PubMed, and Wanfang databases, after which Stata v 12.0 was used to conduct pooled analyses of the resultant data. RESULTS: This meta-analysis included a total of 13 retrospective studies that analyzed 1,731 and 693 malignant and benign PNs, respectively. The respective pooled sensitivity, specificity, PLR, and NLR values for the PET/CT-based studies developed in these models were 88% (95%CI: 0.86-0.91), 78% (95%CI: 0.71-0.85), 4.10 (95%CI: 2.98-5.64), and 0.15 (95%CI: 0.12-0.19). Of these endpoints, the pooled analyses of model sensitivity (I2 = 69.25%), specificity (I2 = 78.44%), PLR (I2 = 71.42%), and NLR (I2 = 67.18%) were all subject to significant heterogeneity. The overall area under the curve value (AUC) value for these models was 0.91 (95%CI: 0.88-0.93). When differential diagnosis was instead performed based on PET results only, the corresponding pooled sensitivity, specificity, PLR, and NLR values were 92% (95%CI: 0.85-0.96), 51% (95%CI: 0.37-0.66), 1.89 (95%CI: 1.36-2.62), and 0.16 (95%CI: 0.07-0.35), with all four being subject to significant heterogeneity (I2 = 88.08%, 82.63%, 80.19%, and 86.38%). The AUC for these pooled analyses was 0.82 (95%CI: 0.79-0.85). CONCLUSIONS: These results suggest that PET/CT-based models may offer diagnostic performance superior to that of PET results alone when distinguishing between benign and malignant PNs.

The influence of flow distribution strategy for the quantification of pressure- and wall shear stress-derived parameters in the coronary artery: A CTA-based computational fluid dynamics analysis.

For image-based computational fluid dynamics (CFD) analysis to characterize the local coronary hemodynamic environment, the accuracy depends on the flow rate which is in turn associated with outlet branches' morphology. A good flow distribution strategy is important to mitigate the effect when certain branches cannot be considered. In this study, stenotic coronary arteries from 13 patients were used to analyze the effect of missing branches and different flow distribution strategies. Pressure- and wall shear stress (WSS)-derived parameters around the stenotic region (ROI) were compared, including fractional flow reserve (CT-FFR), instantaneous wave-free ratio (CT-iFR), resting distal to aortic coronary pressure (CT-Pd/Pa), time-averaged WSS, oscillatory shear index (OSI) and relative residence time (RRT). Three flow distribution strategies were the Huo-Kassab model at distal outlets (Type I), flow distribution based on outlet resistances (Type II), and a developed algorithm distributing flow at each bifurcation until the final outlets (Type III). Results showed that Type III strategy for models with truncated branch(es) had a good agreement in both pressure- and WSS-related results (interquatile range less than 0.12% and 4.02%, respectively) with the baseline model around the ROI. The relative difference of pressure- and WSS-related results were correlated with the flow differences in the ROI to the baseline mode. Type III strategy had the best performance in maintaining the flow in intermediate branches. It is recommended for CFD analysis. Removal of branches distal to a stenosis can be undertaken with an improved performance and maintained accuracy, while those proximal to the ROI should be kept.

Radiomics nomogram based on optimal VOI of multi-sequence MRI for predicting microvascular invasion in intrahepatic cholangiocarcinoma.

OBJECTIVE: Microvascular invasion (MVI) is a significant adverse prognostic indicator of intrahepatic cholangiocarcinoma (ICC) and affects the selection of individualized treatment regimens. This study sought to establish a radiomics nomogram based on the optimal VOI of multi-sequence MRI for predicting MVI in ICC tumors. METHODS: 160 single ICC lesions with MRI scanning confirmed by postoperative pathology were randomly separated into training and validation cohorts (TC and VC). Multivariate analysis identified independent clinical and imaging MVI predictors. Radiomics features were obtained from images of 6 MRI sequences at 4 different VOIs. The least absolute shrinkage and selection operator algorithm was performed to enable the derivation of robust and effective radiomics features. Then, the best three sequences and the optimal VOI were obtained through comparison. The MVI prediction nomogram combined the independent predictors and optimal radiomics features, and its performance was evaluated via the receiver operating characteristics, calibration, and decision curves. RESULTS: Tumor size and intrahepatic ductal dilatation are independent MVI predictors. Radiomics features extracted from the best three sequences (T1WI-D, T1WI, DWI) with VOI10mm (including tumor and 10 mm peritumoral region) showed the best predictive performance, with AUCTC = 0.987 and AUCVC = 0.859. The MVI prediction nomogram obtained excellent prediction efficacy in both TC (AUC = 0.995, 95%CI 0.987-1.000) and VC (AUC = 0.867, 95%CI 0.798-0.921) and its clinical significance was further confirmed by the decision curves. CONCLUSION: A nomogram combining tumor size, intrahepatic ductal dilatation, and the radiomics model of MRI multi-sequence fusion at VOI10mm may be a predictor of preoperative MVI status in ICC patients.

The assessment of pathological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer patients with DCE-MRI and DWI: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to determine the value of dynamic contrast-enhanced-MRI (DCE-MRI) and diffusion-weighted imaging (DWI) in evaluating the pathological response of muscle invasive bladder cancer (MIBC) to neoadjuvant chemotherapy (NAC), and further indirectly compare the diagnostic performance of DCE-MRI and DWI. METHODS: Literatures associated to DCE-MRI and DWI in the evaluation of pathological response of MIBC to NAC were searched from PubMed, Cochrane Library, web of science, and EMBASE databases. The quality assessment of diagnostic accuracy studies 2 tool was used to assess the quality of studies. Pooled sensitivity (SE), specificity (SP), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curves (AUC) with their 95% confidence intervals (CIs) were calculated to evaluate the diagnostic performance of DCE-MRI and DWI in predicting the pathological response to NAC in patients with MIBC. RESULTS: There were 11 studies involved, 6 of which only underwent DCE- MRI examination, 4 of which only underwent DWI examination, and 1 of which underwent both DCE- MRI and DWI examination. The pooled SE, SP, PLR, NLR, DOR of DCE-MRI were 0.88 (95% CI: 0.78-0.93), 0.88 (95% CI: 0.67-0.96), 7.4 (95% CI: 2.3-24.2), 0.14 (95% CI: 0.07-0.27), and 53 (95% CI: 10-288), respectively. The pooled SE, SP, PLR, NLR, DOR of DWI were 0.83 (95% CI: 0.75-0.88), 0.88 (95% CI: 0.81-0.93), 7.1 (95% CI: 4.3-11.7), 0.20 (95% CI: 0.14-0.28), and 36 (95% CI:18-73), respectively. The AUCs of SROC curve for DCE-MRI and DWI were 0.93 (95% CI: 0.91-0.95) and 0.92 (95% CI: 0.89-0.94), respectively. There were no significant differences between DWI and DCE-MRI for SE, SP, and AUC. CONCLUSION: This meta-analysis demonstrated high diagnostic performance of both DCE-MRI and DWI in predicting the pathological response to NAC in MIBC. DWI might be a potential substitute for DCE-MRI, with no significant difference in diagnostic performance between the two. However, caution should be taken when applying our results, as our results were based on indirect comparison. ADVANCES IN KNOWLEDGE: No previous studies have comprehensively analysed the value of DCE-MRI and DWI in evaluating the pathological response to NAC in MIBC. According to the current study, both DCE-MRI and DWI yielded high diagnostic performance, with the AUCs of 0.93 and 0.92, respectively. Indirect comparison no significant difference in the diagnostic performanceof DCE-MRI and DWI.

Clinical and magnetic resonance imaging features predict microvascular invasion in intrahepatic cholangiocarcinoma.

Introduction: Clinical features and magnetic resonance imaging (MRI)-related data are commonly employed in clinical settings and can be used to predict the microvascular invasion (MVI) status of intrahepatic cholangiocarcinoma (ICC) patients. Aim: To generate a clinical and MRI-based model capable of predicting the MVI status of ICC patients. Material and methods: Consecutive ICC patients evaluated from June 2015 to December 2018 were retrospectively enrolled in a training group to establish a predictive clinical MRI model. Consecutive ICC patients evaluated from January 2019 to June 2019 were prospectively enrolled in a validation group to test the reliability of this model. Results: In total, 143 patients were enrolled in the training group, of whom 46 (32.2%) and 96 (67.8%) were MVI-positive and MVI-negative, respectively. Logistics analyses revealed larger tumour size (p = 0.008) and intrahepatic duct dilatation (p = 0.01) to be predictive of MVI positivity, enabling the establishment of the following predictive model: -2.468 + 0.024 × tumour size + 1.094 × intrahepatic duct dilatation. The area under the receiver operating characteristic (ROC) curve (AUC) for this model was 0.738 (p < 0.001). An optimal cut-off value of -1.0184 was selected to maximize sensitivity (71.7%) and specificity (61.9%). When the data from the validation group were incorporated into the predictive model, the AUC value was 0.716 (p = 0.009). Conclusions: Both larger tumour size and intrahepatic duct dilatation were predictive of MVI positivity in patients diagnosed with ICC, and the predictive model developed based on these variables can offer quantitative guidance for assessing the risk of MVI.

Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma.

Background & Aims: Distinct vascular patterns, including microvascular invasion (MVI) and vessels encapsulating tumour clusters (VETC), are associated with poor outcomes of hepatocellular carcinoma (HCC). Imaging surrogates of these vascular patterns potentially help to predict post-resection recurrence. Herein, a prognostic model integrating imaging-based surrogates of these distinct vascular patterns was developed to predict postoperative recurrence-free survival (RFS) in patients with HCC. Methods: Clinico-radiological data of 1,285 patients with HCC from China undergoing surgical resection were retrospectively enrolled from seven medical centres between 2014 and 2020. A prognostic model using clinical data and imaging-based surrogates of MVI and VETC patterns was developed (n = 297) and externally validated (n = 373) to predict RFS. The surrogates (i.e. MVI and VETC scores) were individually built from preoperative computed tomography using two independent cohorts (n = 360 and 255). Whether the model's stratification was associated with postoperative recurrence following anatomic resection was also evaluated. Results: The MVI and VETC scores demonstrated effective performance in their respective training and validation cohorts (AUC: 0.851-0.883 for MVI and 0.834-0.844 for VETC). The prognostic model incorporating serum alpha-foetoprotein, tumour multiplicity, MVI score, and VETC score achieved a C-index of 0.748-0.764 for the developing and external validation cohorts and generated three prognostically distinct strata. For patients at model-predicted medium risk, anatomic resection was associated with improved RFS (p <0.05). By contrast, anatomic resection had no impact on RFS in patients at model-predicted low or high risk (both p >0.05). Conclusions: The proposed model integrating imaging-based surrogates of distinct vascular patterns enabled accurate prediction for RFS. It can potentially be used to identify HCC surgical candidates who may benefit from anatomic resection. Impact and implications: MVI and VETC are distinct vascular patterns of HCC associated with aggressive biological behaviour and poor outcomes. Our multicentre study provided a model incorporating imaging-based surrogates of these patterns for preoperatively predicting RFS. The proposed model, which uses imaging detection to estimate the risk of MVI and VETC, offers an opportunity to help shed light on the association between tumour aggressiveness and prognosis and to support the selection of the appropriate type of surgical resection.

In-depth understanding of higher-order genome architecture in orphan cancer.

The human genome is intertwined, folded, condensed, and gradually constitutes the 3D architecture, thereby affecting transcription and widely involving in tumorigenesis. Incidence and mortality rates for orphan cancers increase due to poor early diagnosis and lack of effective medical treatments, which are now getting attention. In-depth understanding in tumorigenesis has fast-tracked over the last decade, however, the further role and mechanism of 3D genome organization in variant orphan tumorigenesis remains to be fully understood. We summarize for the first time that higher-order genome organization can provide novel insights into the occurrence mechanisms of orphan cancers, and discuss probable future research directions for drug development and anti-tumor therapies.

A chemoenzymatic process for preparation of highly purified dehydroepiandrosterone in high space-time yield.

Dehydroepiandrosterone (DHEA) is an important neurosteroid hormone to keep human hormonal balance and reproductive health. However, DHEA was always produced with impurities either by chemical or biological method and required high-cost purification before the medical use. To address this issue, a novel chemoenzymatic process was proposed and implemented to produce DHEA. An acetoxylated derivate of 4-androstene-3,17-dione (4-AD) was generated by chemical reaction and converted into DHEA by an enzyme cascade reaction combining a hydrolysis reaction with a reduction reaction. The hydrolysis reaction was catalyzed by a commercial esterase Z03 while the reduction reaction was catalyzed by E. coli cells co-expressing a 3ß-hydroxysteroid dehydrogenase SfSDR and a glucose dehydrogenase BtGDH. After the condition optimization, DHEA was synthesized at a 100 mL scale under 100 mM of substrate loading and purified as white powder with the highest space-time yield (4.80 g/L/h) and purity (99 %) in the biosynthesis of DHEA. The successful attempt in this study provides a new approach for green synthesis of highly purified DHEA in the pharmaceutical industry.

Inflammation Disrupts the Brain Network of Executive Function after Cardiac Surgery.

OBJECTIVE: To investigate postoperative functional connectivity (FC) alterations across impaired cognitive domains and their causal relationships with systemic inflammation. BACKGROUND: Postoperative cognitive dysfunction commonly occurs after cardiac surgery, and both systemic and neuroinflammation may trigger its development. Whether FC alterations underlying deficits in specific cognitive domains after cardiac surgery are affected by inflammation remains unclear. METHODS: Seventeen patients, who underwent cardiac valve replacement, completed a neuropsychological test battery and brain MRI scan before surgery and on days 7 and 30 after surgery compared to age-matched healthy controls. Blood samples were taken for tumor necrosis factor-a and interleukin-6 measurements. Seed-to-voxel FC of the left dorsolateral prefrontal cortex (DLPFC) was examined. Bivariate correlation and linear regression models were used to determine the relationships among cognitive function, FC alterations, and cytokines. RESULTS: Executive function was significantly impaired after cardiac surgery. At day 7 follow-up, the surgical patients, compared to the controls, demonstrated significantly decreased DLPFC FC with the superior parietal lobe and attenuated negative connectivity in the default mode network, including the angular gyrus and posterior cingulate cortex. The left DLPFC enhanced the connectivity in the right DLPFC and posterior cingulate cortex, all of which were related to the increased tumor necrosis factor-a and decreased executive function up to day 7 after cardiac surgery. CONCLUSIONS: The decreased FC of executive control network and its anticorrelation with the default mode network may contribute to executive function deficits after cardiac surgery. Systemic inflammation may trigger these transient FC changes and executive function impairments.

Comparison of the effectiveness of anchoring needles and coils in localizing multiple nodules in the lung.

BACKGROUND: Recently, a new type of pulmonary nodule positioning needle has been adopted clinically. We aimed to evaluate the efficacy and safety of a new type of localization needles compared with coils for the simultaneous localization of multiple pulmonary nodules guided by computed tomography (CT) prior to video-assisted thoracoscopic surgery (VATS). MATERIALS AND METHODS: From January 2021 to March 2022, 87 pulmonary nodules from 40 patients were localized using the new localization needle. From January 2020 to December 2020, 68 pulmonary nodules in 31 patients were localized using coils. The relative outcomes were compared. RESULTS: The success rate of pulmonary nodule localization in the needle group was 97.7% while that in the coil group was 98.5%. In the needle group, the time needed to locate the first nodule was significantly shorter than in the coil group (10.9 min vs. 17.2 min, P = 0.001). Moreover, the time needed per patient was also significantly shorter for the needle group compared with the coil group (23.7 min vs. 30 min, P = 0.017). The incidence of pneumothorax in the needle group was 25.0% vs. 12.9% in the coil group (P = 0.204). The rate of pulmonary hemorrhage in the needle group was 40.0% vs. 32.3% in the coil group (P = 0.502). The success rate of VATS wedge resection was 100% in both groups. CONCLUSION: Both disposable pulmonary nodule localization needles and coils are safe and effective for CT-guided localization of multiple pulmonary nodules of the same stage prior to VATS. However, the use of needles is time-saving compared with the use of coils. The coil localization may exhibit better safety than needle localization.