Differential effect of tumor budding on the benefit of adjuvant chemotherapy in stage II colorectal cancer: a retrospective observational study.

Background: Tumor budding (TB) has been shown to be a poor prognostic indicator after colorectal cancer (CRC) surgery. The aim of the present study is to evaluate the predictive role of morphological features (e.g., the number, structure, and location of tumor buds, and their reaction with the extracellular mesenchyme) in postoperative adjuvant chemotherapy in surgically resectable stage II CRC. Methods: Between 2016 and 2019, 336 patients with stage II CRC who underwent radical surgery were enrolled in this study. TB status was determined according to the criteria adopted at the 2016 International Tumor Budding Consensus Conference (ITBCC). We retrospectively recorded all the clinical and pathological data and assessed the effect of different types of TB status on patients' recurrence-free survival (RFS) and overall survival (OS). Results: Of the 336 patients, 173, 88, and 75 were budding grade 1 (BD1), BD2, and BD3, respectively. The 5-year RFS rates were 84.6%, 81.2%, and 68.0% (P=0.01), and the 5-year OS rates were 91.0%, 83.3%, and 76.2% (P=0.007) in BD1, BD2, and BD3, respectively. TB grade was strongly associated with vascular invasion status and mucinous adenocarcinoma, and BD3 was detected in 51.7% of patients with positive vascular invasion. The multivariate analysis showed that only age, perineural invasion, and TB grade [BD2 vs. BD1, hazard ratio (HR) =1.468, 95% confidence interval (CI): 0.703-3.063, P=0.30; BD3 vs. BD1, HR =2.310, 95% CI: 1.154-4.625, P=0.01] had an independent effect on RFS. In addition, the Kaplan-Meier curve analysis showed that BD3 patients had the worst RFS (P=0.01). The OS of the adjuvant chemotherapy group was significantly improved compared to that of the surgery-only group in the BD1/2 patients (HR =0.278, 95% CI: 0.114-0.676, P=0.005) but not in the BD3 patients with significant interaction (Pinteraction=0.03). Conclusions: Our results indicate that TB could play a subsidiary role in selecting stage II CRC patients who could achieve a favorable prognosis with chemotherapy.

A mini-review-cancer energy reprogramming on drug resistance and immune response.

With the growing interest to harness cancer metabolism and energy reprogramming, this mini review aimed to explain the metabolic programming revealing the mechanisms regarding the treatment resistance. This mini review summarized the prominent cancer metabolic reprogramming on macromolecules. In addition, metabolic reprogramming explaining immune response and treatment resistance as well as energy reprogramming mechanisms are briefly discussed. Finally, some prospects in MR for reversing cancer drug resistance are highlighted.

Immersive Virtual Reality Versus Video Distraction for the Management of Emergence Delirium in Children: A Randomized Controlled Study.

PURPOSE: Emergence delirium (ED) presents challenges for both parents and health care providers in pediatric surgical settings. This study aims to evaluate the effectiveness of immersive virtual reality (VR) distraction and video distraction combined with parental presence in reducing ED in preschool-aged children undergoing elective surgery. DESIGN: A prospective, randomized, controlled clinical trial was conducted with 90 children ages 4 to 7. Participants were randomly assigned to three groups: VR distraction (group V), tablet video distraction with parental presence (group T), and standard care (group C). The primary endpoints were the incidence of ED and Pediatric Anesthesia Emergence Delirium Scale scores, with secondary measures encompassing scores from the Parental Separation Anxiety Scale and the Faces, Legs, Activity, Cry, Consolability (FLACC) scale. METHODS: Participants were assigned to one of the three intervention groups, and relevant scales were used to assess ED, parental separation anxiety, and postoperative pain. The immersive VR distraction and video distraction with parental presence interventions were compared against standard care. FINDINGS: Immersive VR distraction significantly reduced the incidence of ED (6.67% in group V vs 40% in group T and 60% in group C), and the incidence of ED in group V was notably lower than in the other groups (P = .023 vs group T and P = .004 vs group C). Children in group V displayed significantly lower FLACC compared with the other groups as well (P < .05). However, no significant differences between the 3 groups were observed in perioperative anxiety as assessed by the Parental Separation Anxiety Scale scores (P = .27). CONCLUSIONS: This study underscores the potential of immersive VR distraction as an effective intervention for mitigating ED in pediatric surgical patients. The findings suggest that incorporating VR technology during the perioperative period can positively impact postoperative outcomes. Further research in diverse surgical contexts is recommended to validate these findings and explore the broader applicability of VR distraction in pediatric health care settings.

YinChen WuLing powder attenuates non-alcoholic steatohepatitis through the inhibition of the SHP2/PI3K/NLRP3 pathway.

Background: YinChen WuLing Powder (YCWLP) has been recommended by consensus for the treatment of non-alcoholic steatohepatitis (NASH); nevertheless, its specific pharmacological mechanisms remain to be elucidated. This study aims to dissect the mechanisms underlying the therapeutic effects of YCWLP on NASH using a hybrid approach that encompasses network pharmacology, molecular docking, and in vitro experimental validation. Methods: We compiled the chemical constituents of YCWLP from the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform (TCMSP), while potential targets were predicted using the SwissTargetPrediction database. To identify NASH-related candidate targets, comprehensive retrieval was carried out using five authoritative databases. Protein-Protein Interaction (PPI) networks of direct targets of YCWLP in NASH treatment were then constructed using the String database, and functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, were conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Core targets were discerned using the Molecular Complex Detection (MCODE) and cytoHubba algorithms. Subsequently, molecular docking of key compounds to core targets was conducted using AutoDock software. Moreover, we established a free fatty acid-induced HepG2 cell model to simulate NASH in vitro, with YCWLP medicated serum intervention employed to corroborate the network pharmacology-derived hypotheses. Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), and Western blotting analyses was employed to investigate the lipid, hepatic enzyme, SHP2/PI3K/NLRP3 signaling pathway and associated cytokine levels. Results: The network pharmacology analysis furnished a list of 54 compounds from YCWLP and 167 intersecting targets associated with NASH. Through analytic integration with multiple algorithms, PTPN11 (also known as SHP2) emerged as a core target of YCWLP in mitigating NASH. The in vitro experiments validated that 10% YCWLP medicated serum could remarkably attenuate levels of total cholesterol (TC, 1.25 vs. 3.32) and triglyceride (TG, 0.23 vs. 0.57) while ameliorating alanine aminotransferase (ALT, 7.79 vs. 14.78) and aspartate aminotransferase (AST, 4.64 vs. 8.68) leakage in NASH-afflicted cells. In addition, YCWLP significantly enhanced the phosphorylation of SHP2 (0.55 vs. 0.20) and downregulated the expression of molecules within the SHP2/PI3K/NLRP3 signaling axis, including p-PI3K (0.42 vs. 1.02), NLRP3 (0.47 vs. 0.93), along with downstream effectors-cleaved Caspase-1 (0.21 vs. 0.49), GSDMD-NT (0.24 vs. 0.71), mature interleukin-1ß (IL-1ß, 0.17 vs. 0.48), pro-IL-1ß (0.49 vs. 0.89), mature interleukin-18 (IL-18, 0.15 vs. 0.36), and pro-IL-18 (0.48 vs. 0.95). Conclusion: Our research reveals that YCWLP exerts therapeutic effects against NASH by inhibiting lipid accumulation and inflammation, which involves the attenuation of pyroptosis via the SHP2/PI3K/NLRP3 pathway.

In-Situ Dynamic Carburization of Mo Oxide with Unprecedented High CO Formation Rate in Reverse Water-Gas Shift Reaction.

In-situ construction of active structure under reaction conditions is highly desired but still remains challenging in many important catalytic processes. Herein, we observe structural evolution of molybdenum oxide (MoOx) into highly active molybdenum carbide (MoCx) during reverse water-gas shift (RWGS) reaction. Surface oxygen atoms in various Mo-based catalysts are removed in H2-containing atmospheres and then carbon atoms can accumulate on surface to form MoCx phase with the RWGS reaction going on, both of which are enhanced by the presence of intercalated H species or Pt-dopants in MoOx. The structural evolution from MoOx to MoCx is accompanied by enhanced CO2 conversion, which is positively correlated with the surface C/Mo ratio but negatively with the surface O/Mo ratio. As a result, an unprecedented CO formation rate of 7544.6 mmol·gcatal-1·h-1 at 600 °C has been achieved over in-situ carbonized H-intercalated MoO3 catalyst, which is even higher than those from noble metal catalysts. During 100 h stability test only a minimal deactivation rate of 2.3% is observed.

Structure-function interrelationships and associated neurotransmitter profiles in drug-naïve benign childhood epilepsy with central-temporal spikes patients.

OBJECTIVES: To explore the interrelationships between structural and functional changes as well as the potential neurotransmitter profile alterations in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients. METHODS: Structural magnetic resonance imaging (sMRI) and resting-state functional MRI data from 20 drug-naïve BECTS patients and 33 healthy controls (HCs) were acquired. Parallel independent component analysis (P-ICA) was used to identify covarying components among gray matter volume (GMV) maps and fractional amplitude of low-frequency fluctuations (fALFF) maps. Furthermore, we explored the spatial correlations between GMV/fALFF changes derived from P-ICA and neurotransmitter maps in JuSpace toolbox. RESULTS: A significantly positive correlation (p < 0.001) was identified between one structural component (GMV_IC6) and one functional component (fALFF_IC4), which showed significant group differences between drug-naïve BECTS patients and HCs (GMV_IC6: p < 0.01; fALFF_IC4: p < 0.001). GMV_IC6 showed increased GMV in the frontal lobe, temporal lobe, thalamus, and precentral gyrus as well as fALFF_IC4 had enhanced fALFF in the cerebellum in drug-naïve BECTS patients compared to HCs. Moreover, significant correlations between GMV alterations in GMV_IC6 and the serotonin (5HT1a: p < 0.001; 5HT2a: p < 0.001), norepinephrine (NAT: p < 0.001) and glutamate systems (mGluR5: p < 0.001) as well as between fALFF alterations in fALFF_IC4 and the norepinephrine system (NAT: p < 0.001) were detected. CONCLUSION: The current findings suggest co-altered structural/functional components that reflect the correlation of language and motor networks as well as associated with the serotonergic, noradrenergic, and glutamatergic neurotransmitter systems. CLINICAL RELEVANCE STATEMENT: The relationship between anatomical brain structure and intrinsic neural activity was evaluated using a multimodal fusion analysis and neurotransmitters which might provide an important window into the multimodal neural and underlying molecular mechanisms of benign childhood epilepsy with central-temporal spikes. KEY POINTS: Structure-function relationships in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients were explored. The interrelated structure-function components were found and correlated with the serotonin, norepinephrine, and glutamate systems. Co-altered structural/functional components reflect the correlation of language and motor networks and correlate with the specific neurotransmitter systems.

Enhancement of Pulmonary Function and Reduction of Complications Through EIT-Guided Yoga Breathing Exercise After Esophagectomy.

BACKGROUND This study aimed to investigate the impact of EIT-guided yoga breathing training on postoperative pulmonary complications (PPCs) for esophageal cancer patients. MATERIAL AND METHODS Total of 62 patients underwent radical resections of esophageal cancer. Esophageal cancer patients were randomized to the standard care group, or the intervention group receiving an additional complete breathing exercise under the guidance of EIT in AICU. Following extubation after the esophagectomy, pulmonary functions were evaluated by EIT with center of ventilation (CoV), dependent silent spaces (DSS), and non-dependent silent spaces (NSS). RESULTS Sixty-one older esophageal cancer patients (31 in the Control group and 30 in the EIT group) were included in the final analysis. Forty-four patients experienced pulmonary complications after esophagectomy, 27 (87.1%) in the Control group and 17 (36.7%) in the EIT group (RR, 0.42 (95% CI: 0.26, 0.69). The most common pulmonary complication was pleural effusion, with an incidence of 30% in the EIT group and 74.2% in the Control group, with RR of 0.40 (95% CI: 0.23, 0.73). Time for the first pulmonary complication was significantly longer in the EIT group than in the Control group (hazard ratio, HR, 0.43; 95% CI 0.21 to 0.87; P=0.019). Patients in the EIT group had significantly higher scores in CoV, DSS, and NSS than in the Control group. CONCLUSIONS Guided by EIT, the addition of the postoperative breathing exercise to the standardized care during AICU could further improve pulmonary function, and reduce postoperative pulmonary complications after esophagectomy.

Enhancing diabetic wound healing with a pH/glucose dual-responsive hydrogel for ROS clearance and antibacterial activity.

Currently, the treatment of diabetic wounds in clinical practice is still unsatisfactory due to the risks of oxidative damage and bacterial infection during the healing process. An optimal wound dressing should exhibit robust capabilities in scavenging reactive oxygen species (ROS) and combatting bacterial growth. In this study, we utilized borax as a crosslinker and prepared a pH/glucose dual-responsive composite hydrogel based on poly(vinyl alcohol) (PVA), sodium alginate (SA), and tannic acid (TA). This hydrogel, loaded with cerium dioxide, serves as an effective ROS scavenger, promoting wound closure by reducing the level of ROS in the wound area. Additionally, the hydrogel can release the antibacterial drug ofloxacin in response to the low pH and high glucose microenvironment in infected wounds. Results from skin defect model in diabetic mice demonstrated this ROS-scavenging and antibacterial hydrogel can suppress inflammation and accelerate wound healing. In summary, our work provides a new perspective on a local and stimulus-responsive drug delivery strategy for treating diabetic wounds.

Water-assisted oxidative redispersion of Cu particles through formation of Cu hydroxide at room temperature.

Sintering of active metal species often happens during catalytic reactions, which requires redispersion in a reactive atmosphere at elevated temperatures to recover the activity. Herein, we report a simple method to redisperse sintered Cu catalysts via O2-H2O treatment at room temperature. In-situ spectroscopic characterizations reveal that H2O induces the formation of hydroxylated Cu species in humid O2, pushing surface diffusion of Cu atoms at room temperature. Further, surface OH groups formed on most hydroxylable support surfaces such as γ-Al2O3, SiO2, and CeO2 in the humid atmosphere help to pull the mobile Cu species and enhance Cu redispersion. Both pushing and pulling effects of gaseous H2O promote the structural transformation of Cu aggregates into highly dispersed Cu species at room temperature, which exhibit enhanced activity in reverse water gas shift and preferential oxidation of carbon monoxide reactions. These findings highlight the important role of H2O in the dynamic structure evolution of supported metal nanocatalysts and lay the foundation for the regeneration of sintered catalysts under mild conditions.

Brain structural changes and molecular analyses in children with benign epilepsy with centrotemporal spikes.

BACKGROUND: Benign epilepsy with centrotemporal spikes (BECTS) is a common childhood epilepsy syndrome, accompanied by behavioral problems and cognitive impairments. Previous studies of BECTS-related brain structures applied univariate analysis and showed inconsistent results. And neurotransmitter patterns associated with brain structural alterations were still unclear. METHODS: Structural images of twenty-one drug-naïve children with BECTS and thirty-five healthy controls (HCs) were scanned. Segmented gray matter volume (GMV) images were decomposed into independent components (ICs) using the source-based morphometry method. Then spatial correlation analyses were applied to examine possible relationships between GMV changes and neurotransmitter systems. RESULTS: Compared with HCs, drug-naïve children with BECTS showed increased volume in one GMV component (IC7), including bilateral precentral gyrus, bilateral supplementary motor area, left superior frontal cortex, bilateral middle/ inferior frontal cortex and bilateral anterior/ middle cingulate cortex. A positive correlation was observed between one GMV component (IC6) and seizure frequency. There were significantly positive correlations between abnormal GMV in IC7 and serotonergic, GABAergic and glutamatergic systems. CONCLUSION: These findings provided further evidence of changed GMV in drug-naïve children with BECTS related to their behavioral problems and cognitive impairments, and associated neurotransmitters which could help to better understand neurobiological mechanisms and underlying molecular mechanisms of BECTS. IMPACT: The article provides further evidence of changed gray matter volume in drug-naïve children with BECTS related to their behavioral problems and cognitive impairments as well as associated neurotransmitters. Most literature to date has applied univariate analysis and showed inconsistent results, and neurotransmitter patterns associated with brain structural alterations were still unclear. Therefore, this article uses multivariate method and JuSpace toolbox to fill the gap. Significantly increased gray matter volume was found in drug-naïve children with BECTS compared with healthy controls. Abnormal gray matter volume was significantly correlated with clinical data and specific neurotransmitters.

Relationship between fear of COVID-19 and mental health of Chinese nurses: The mediating effects of psychological capital and burnout.

AIM: The aim of the study was to investigate the correlation between fear of COVID-19 and mental health of nurses and the effects of psychological capital and burnout in this relation. DESIGN: A cross-sectional study. METHODS: The online surveys were conducted among mainland Chinese nurses. Participants (n = 445; average age 32.89 ± 6.76 years) completed an online-questionnaire based on the Fear of COVID-19 Scale, the Psychological Capital Scale, Maslach Burnout Inventory Human Services Survey for Medical Professionals Scale and the 12-Item Short Form Health Survey. Data analysis was conducted by Pearson's correlation analysis, Harman single-factor test and the bootstrap method for mediating effect testing. RESULTS: (1) The study demonstrated a significant direct effect of fear of COVID-19 on nurses' mental health, as well as on mediating factors such as burnout and psychological capital. (2) Regression analyses confirmed that while psychological capital bolstered mental health, burnout undermined it, with fear of COVID-19 further imposing a negative influence. (3) Fear of COVID-19 exerted an effect on the mental health of nurses by the independent and chain intermediary functions of psychological capital and burnout, resulting in a total mediating effect of -0.233.

Synergistic cerium oxide nanozymes: targeting DNA damage and alleviating tumor hypoxia for improved NSCLC radiotherapy efficiency.

Radiotherapy (RT) is one of the important treatment modalities for non-small cell lung cancer (NSCLC). However, the maximum radiation dose that NSCLC patient can receive varies little. Therefore, the exploitation of novel RT sensitization approaches is a critical need for the clinical treatment. RT resistance in NSCLC is linked to tumor microenvironment (TME) hypoxia, cell cycle arrest and associated genetic alterations. Here, we designed a novel method for targeted delivery of quercetin (QT) and CeO2 to enhance RT sensitivity. We loaded QT into CeO2@ZIF-8-HA nanoparticles to prevent its degradation in the circulatory system and successfully delivered QT and CeO2 targeted to NSCLC tumors. Under the protection and targeted delivery of Zeolitic Imidazolate Framework-8 (ZIF-8), the nanocomplexes exhibited excellent catalytic mimetic activity in decomposing H2O2 into O2, thus significantly reversing the hypoxia of TME, while the radiosensitizer QT caused DNA damage directly after RT. In a subcutaneous tumor model, CeO2@ZIF-8-HA overcame radiation resistance and enhanced therapeutic efficacy. This multiple sensitization strategy combining delivery of QT and CeO2@ZIF-8-HA nanozymes opens a promising approach for RT of NSCLC.

Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation.

Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

Structure of brain grey and white matter in infants with spastic cerebral palsy and periventricular white matter injury.

AIM: To investigate the possible covariation of grey matter volume (GMV) and white matter fractional anisotropy in infants with spastic cerebral palsy (CP) and periventricular white matter injury. METHOD: Thirty-nine infants with spastic CP and 25 typically developing controls underwent structural magnetic resonance imaging and diffusion tensor imaging. Multimodal canonical correlation analysis with joint independent component analysis were used to capture differences in GMV and fractional anisotropy between groups. Correlation analysis was performed between imaging findings and clinical features. RESULTS: Infants with spastic CP showed one joint group-discriminating component (i.e. GMV-fractional anisotropy) associated with regions in the cortico-basal ganglia-thalamo-cortical loop and in the corpus callosum compared to typically developing controls and one modality-specific group-discriminating component (i.e. GMV). Significant negative correlations were found between loadings in certain regions and the motor function score in spastic CP. INTERPRETATION: In infants with spastic CP, covarying GMV-fractional anisotropy and altered GMV in specific regions were implicated in motor dysfunction, which confirmed that simultaneous GMV and fractional anisotropy changes underly motor deficits, but might also extend to sensory, cognitive, or visual dysfunction. These findings also suggest that multimodal fusion analysis allows for a more comprehensive understanding of the relevance between grey and white matter structures and its crucial role in the neuropathological mechanisms of spastic CP.

Snap-on Adaptor for Microtiter Plates to Enable Continuous-Flow Microfluidic Screening and Harvesting of Crystalline Materials.

Microtiter plate assay is a conventional and standard tool for high-throughput (HT) screening that allows the synthesis, harvesting, and analysis of crystals. The microtiter plate screening assays require a small amount of solute in each experiment, which is adequate for a solid-state crystal analysis such as X-ray diffraction (XRD) or Raman spectroscopy. Despite the advantages of these high-throughput assays, their batch operational nature results in a continuous decrease in supersaturation due to crystal nucleation and growth. Continuous-flow microfluidic mixer devices have evolved as an alternate technique for efficiently screening crystals under controlled supersaturation. However, such a microfluidic device requires a minimum of two inlets per micromixer to create cyclonic flow, thereby creating physical limitations for implementing such a device for HT screening. Additionally, the monolithic design of these microfluidic devices makes it challenging to harvest crystals for post-screening analysis. Here, we develop a snap-on adapter that can be reversibly attached to a microtiter plate and convert it into a continuous-flow microfluidic mixer device. The integration of the snap-on adapter with a flow distributor and concentration gradient generator provides greater control over screening conditions while minimizing the number of independent inlets and pumps required. The three-dimensional (3D)-printed snap-on adaptor is plugged into a 24-well plate assay to demonstrate salt screening of naproxen crystals. Different naproxen salts are crystallized using four different salt formers (SFs)-sodium hydroxide, potassium hydroxide, pyridine, and arginine-and four different solvents-ethanol, methanol, isopropyl alcohol, and deionized water. The wells are further inspected under an optical microscope to identify their morphological forms and yields. The crystals are then harvested for solid-state characterization using XRD and Fourier transform infrared spectroscopy, followed by measurement of their dissolution rates. The flexibility of the snap-on adapter to fit on a wide range of microtiter plates and the ease in harvesting and analyzing crystals postscreening are two significant advantages that make this device versatile for various applications.

HILPDA-mediated lipidomic remodelling promotes radiotherapy resistance in nasopharyngeal carcinoma by accelerating mitophagy.

Radiotherapy resistance is a major obstacle to nasopharyngeal carcinoma (NPC) therapy and contributes to tumour recurrence and metastasis. Lipid metabolism is a key regulatory mechanism in cancer biology; however, its role in NPC radiotherapy resistance remains unclear. In this study, we identified hypoxia-inducible lipid droplet-associated protein (HILPDA) as a newly discovered regulator of radioresistance that induces not only lipid droplet (LD) formation but also intracellular lipid remodelling, notably changing mitochondrial cardiolipin (CL) levels. Additionally, we found that the upregulation of CL promotes mitophagy in response to irradiation exposure. Mechanistically, HILPDA inhibits PINK1-mediated CLS1 ubiquitination and degradation. The combination of a mitophagy inhibitor and irradiation significantly increases the radiosensitivity of NPC cells. Human cancer-derived data confirmed that the HILPDA-CLS1 pathway promotes NPC radioresistance. Collectively, these findings suggest that HILPDA plays a critical role in promoting NPC radioresistance and might be targeted to overcome radiotherapeutic resistance in NPC patients in the clinic.

Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1.

BACKGROUND: During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)-like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. METHODS: The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2-binding proteins were screened using co-immunoprecipitation, quantitative label-free liquid chromatography-tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). RESULTS: The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin-mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP-1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. CONCLUSION: These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

Disruption of Periaqueductal Gray-default Mode Network Functional Connectivity in Patients with Crohn's Disease with Abdominal Pain.

Abdominal pain in Crohn's disease (CD) has been known to be associated with changes in the central nervous system. The periaqueductal gray (PAG) plays a well-established role in pain processing. However, the role of PAG-related network and the effect of pain on the network in CD remain unclear.Resting-state functional magnetic imaging (fMRI) data were collected from 24 CD patients in remission with abdominal pain, 24 CD patients without abdominal pain and 28 healthy controls (HCs). Using the subregions of PAG (dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG)) as seeds, the seed-based FC maps were calculated and one-way analysis of variance (ANOVA) was performed to investigate the differences among the three groups.Results showed that the group differences were mainly involved in the FC of the vlPAG with the precuneus, medial prefrontal cortex (mPFC) as well as orbitofrontal cortex (OFC), and the FC of the right lateral PAG (lPAG) with the precuneus, inferior parietal lobule (IPL), angular gyrus and premotor cortex. The FC values of all these regions decreased successively in the order of HCs, CD without abdominal pain and CD with abdominal pain. The pain score was negatively correlated with the FC of the l/vlPAG with the precuneus, angular gyrus and mPFC in CD patients with abdominal pain.This study implicated the disrupt communication between the PAG and the default mode network (DMN). These findings complemented neuroimaging evidence for the pathophysiology of visceral pain in CD patients.

Altered functional connectivity density and structural covariance networks in women with premenstrual syndrome.

Background: Premenstrual syndrome (PMS) is a menstrual-related disorder, characterized by physical, emotional, behavioral and cognitive symptoms. However, the neuropathological mechanisms of PMS remain unclear. This study aimed to investigate the frequency-specific functional connectivity density (FCD) and structural covariance in PMS. Methods: Functional and T1-weighted structural data were obtained from 35 PMS patients and 36 healthy controls (HCs). This study was a cross-sectional and prospective design. The local/long-range FCD (LFCD/LRFCD) across slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) bands were computed, and two-way analysis of variance (ANOVA) was performed to ascertain the main effects of group and interaction effects between group and frequency band. Receiver operating characteristic (ROC) curve was performed to investigate reliable biomarkers for identifying PMS from HCs. Based on the ROC results, characterized the changes of whole-brain structural covariance patterns of striatum subregions in two groups. Correlation analysis was applied to examine relationships between the clinical symptoms and abnormal brain regions. Results: Compared with HCs, PMS patients exhibited: (I) aberrant functional communication in the middle cingulate cortex and precentral gyrus; (II) significant frequency band-by-group interaction effects of the striatum, thalamus and orbitofrontal cortex; (III) the better classification ability of the LFCD in the striatum in ROC analysis (slow-5); (IV) decreased gray matter volumes in the caudate subregions and decreased structural associations of between the caudate subregions and frontal cortex; (V) the LFCD value in thalamus were significantly negatively correlated with the sleep problems (slow-5). Conclusions: Based on multi-modal magnetic resonance imaging (MRI) analysis, this study might imply the aberrant emotional regulation and cognitive function related to menstrual cycle in PMS and improve our understanding of the pathophysiologic mechanism in PMS from novel perspective.