Search

Background: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. Objective: This research explored the effectiveness of integrating anlotinib (a broad‐spectrum tyrosine kinase inhibitor) with programmed death‐1 (PD‐1) blockade and offers mechanistic insights into more effective strategies for treating HCC. Methods: Using patient‐derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD‐1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time‐of‐flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. Results: The combination of anlotinib with an anti‐PD‐1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF‐1α signaling axis. CD8+ T‐cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti‐PD‐1 therapy in patients with HCC. Conclusions: Our findings highlight anlotinib's potential to augment the efficacy of anti‐PD‐1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14‐mediated CD8+ T‐cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. Highlights: Synergistic effects of anlotinib and anti‐PD‐1 immunotherapy demonstrated in HCC preclinical models.Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF‐1α pathway.CXCL14 upregulation via TFRC suppression boosts CD8+ T‐cell recruitment.TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti‐PD‐1‐based therapies in advanced HCC patients. [ABSTRACT FROM AUTHOR]

With rapid development and mature of single‐cell measurements, single‐cell biology and pathology become an emerging discipline to understand the disease. However, it is important to address concerns raised by clinicians as to how to apply single‐cell measurements for clinical practice, translate the signals of single‐cell systems biology into determination of clinical phenotype, and predict patient response to therapies. The present Perspective proposes a new system coined as the clinical artificial intelligent single‐cell (caiSC) with the dynamic generator of clinical single‐cell informatics, artificial intelligent analysers, molecular multimodal reference boxes, clinical inputs and outs, and AI‐based computerization. This system provides reliable and rapid information for impacting clinical diagnoses, monitoring, and prediction of the disease at the single‐cell level. The caiSC represents an important step and milestone to translate the single‐cell measurement into clinical application, assit clinicians' decision‐making, and improve the quality of medical services. There is increasing evidence to support the possibility of the caiSC proposal, since the corresponding biotechnologies associated with caiSCs are rapidly developed. Therefore, we call the special attention and efforts from various scientists and clinicians on the caiSCs and believe that the appearance of the caiSCs can shed light on the future of clinical molecular medicine. [ABSTRACT FROM AUTHOR]

Targeted mass spectrometry (MS) holds promise for precise protein and protein‐representative peptide identification and quantification, enhancing disease diagnosis. However, its clinical application is hindered by complex data analysis and expert review requirements. It is hypothesized that machine learning (ML) models can automate data analysis to accelerate the clinical application of MS. The approach involves an ML‐driven pipeline that extracts statistical and morphological features from an MS target region and feeds these features into ML algorithms to generate and assess predictive models. The findings demonstrate ML prediction models exhibit superior performance when trained on extracted features versus raw spectra intensity data and that random forest models exhibit robust classification performance in both internal and external validation datasets. These models remain effective across varying training dataset sizes and positive sample rates and are enhanced by a nested active learning approach. This approach can thus revolutionize clinical MS applications. [ABSTRACT FROM AUTHOR]

Hepatocellular adenoma (HCA) represents a rare benign hepatic neoplasm with potential for malignant transformation into hepatocellular carcinoma (HCC), yet the underlying mechanism remains elusive. In this study, we investigated the genomic landscape of this process to identify therapeutic strategies for blocking malignant transformation. Using micro‐detection techniques, we obtained specimens of adenoma, cancerous neoplasm and adjacent normal liver from three patients undergoing hepatic resection surgery. Whole‐exome sequencing (WES) was performed, and genomic interactions between HCA and HCC components within the same tumour were evaluated using somatic variant calling, copy number variation (CNV) analysis, clonality evaluation and mutational signature analysis. Our results revealed genomic heterogeneity among patient cases, yet within each sample, HCA and HCC tissues exhibited a similar mutational landscape, suggesting a high degree of homology. Using nonnegative matrix factorization and phylogenetic trees, we identified shared and distinct mutational characteristics and uncovering necessary pathways associated with HCA–HCC malignant transformation. Remarkably, we found that HCA and HCC shared a common monoclonal origin while displaying significant genetic diversity within HCA–HCC tumours, indicating fundamental genetic connections or evolutionary pathways between the two. Moreover, elevated immune therapy‐related markers in these patients suggested heightened sensitivity to immune therapy, providing novel avenues for the treatment of hepatic malignancies. This study sheds light on the genetic mechanisms underlying HCA–HCC progression, offering potential targets for therapeutic intervention and highlighting the promise of immune‐based therapies in managing hepatic malignancies. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorders (FASD) include a range of neurocognitive and behavioral impairments resulting from prenatal alcohol exposure (PAE). Among the PAE‐related cognitive deficits, number processing is particularly affected. This study examines alterations in number processing networks and whether changes in functional connectivity mediate the adverse effects of PAE on arithmetic performance. Methods: Magnetic resonance imaging (MRI) was acquired in 57 children (mean (SD) age = 11.3 (+0.9) yr), 38 with FASD (19 fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 heavily exposed (HE)) and 19 controls. Whole‐brain correlation analyses were performed from five seeds located in regions involved in number processing. Results: Children with FAS/PFAS showed dose‐dependent reductions in resting state functional connectivity between the seed in the right (R) posterior superior parietal lobule and a cluster in the left (L) inferior frontal gyrus, and between a seed in the R horizontal intraparietal sulcus and clusters in the R precentral gyrus and L cerebellar lobule VI. HE children showed lower resting state functional connectivity in a subset of these regions. Lower functional connectivity in the two fronto‐parietal connections partially mediated the adverse effects of PAE on arithmetic performance. Conclusion: This study demonstrates PAE‐related functional connectivity impairments in functional networks involved in number processing. The weaker connectivity between the R posterior superior parietal lobule and the L inferior frontal gyrus suggests that impaired verbal processing and visuospatial working memory may play a role in number processing deficits, while weaker connectivity between the R intraparietal sulcus and the R precentral gyrus points to poorer finger‐based numerical representation, which has been linked to arithmetic computational skills. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood‐based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. Methods: A three‐phase multicentre study was conducted to screen, optimise and validate HCC‐specific differentially methylated regions (DMRs) using next‐generation sequencing and quantitative methylation‐specific PCR (qMSP). Results: Genome‐wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre‐ and postoperative plasma samples from 103 HCC patients and correlated with 2‐year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p <.001). Conclusions: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC‐specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at‐risk populations. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming induced by Epstein‐Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV‐associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV‐associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D‐2HG, and serum D‐2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)‐driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α‐KG, which inhibits the expression of EBV lytic genes with CpG‐containing ZREs and the latent‐lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC. [ABSTRACT FROM AUTHOR]

Background: Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline‐rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole‐exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput. Methods: Patients meeting the diagnosis criteria of PKD with negative results of PRRT2‐Sanger sequencing and WES were included in this study. Mutation screening and targeted high‐throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations. Results: Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high‐throughput sequencing from 26 PKD patients with negative results of PRRT2‐Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression. Conclusion: Based on the above studies, we emphasize the routine targeted high‐throughput sequencing of the c.649 site in the PRRT2 gene in so‐called genetic‐testing‐negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis. [ABSTRACT FROM AUTHOR]

Hypoxia, as a distinctive feature of tumors, is closely related to tumor recurrence, metastasis, and treatment resistance. Metal-organic framework (MOF) exhibits an increasing number of advantages in cancer therapy owing to its porous structure, large specific surface area, and tunable function. The MOF nanocomposites constructed by adjusting components can effectively overcome tumor hypoxia and significantly enhance the anti-tumor effect. In this review, the hypoxic characteristics of tumors and current strategies for constructing MOF nanocomposites that can overcome tumor hypoxia are summarized, including for delivering O2 or endogenously generating O2 to elevate intra-tumor O2 content; inhibiting HIF-1 and its induced products to alleviate tumor hypoxia; reducing cellular aerobic respiration to decrease cellular O2 consumption, and exacerbating hypoxia to improve the efficacy of hypoxia-activated pre-drugs. At the same time, the applications of MOF nanocomposites applied to overcome tumor hypoxia in different therapeutic methods at the present stage are described, and finally, the challenges and opportunities in further development of MOF nanocomposites are discussed. [ABSTRACT FROM AUTHOR]

Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation‐induced double‐stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation‐induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS‐STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC‐derived RECQL4 disrupts cGAS‐STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC. [ABSTRACT FROM AUTHOR]

Carbon dioxide reduction reaction (CO2RR) provides an efficient pathway to convert CO2 into desirable products, yet its commercialization is greatly hindered by the huge energy cost due to CO2 loss and regeneration. Performing CO2RR under acidic conditions containing alkali cations can potentially address the issue, but still causes (bi)carbonate deposition at high current densities, compromising product Faradaic efficiencies (FEs) in present‐day acid‐fed membrane electrode assemblies. Herein, we present a strategy using a positively charged polyelectrolyte—poly(diallyldimethylammonium) immobilized on graphene oxide via electrostatic interactions to displace alkali cations. This enables a FE of 85 %, a carbon efficiency of 93 %, and an energy efficiency (EE) of 35 % for CO at 100 mA cm−2 on modified Ag catalysts in acid. In a pure‐water‐fed reactor, we obtained a 78 % CO FE with a 30 % EE at 100 mA cm−2 at 40 °C. All the performance metrics are comparable to or even exceed those attained in the presence of alkali metal cations. [ABSTRACT FROM AUTHOR]

A study published in the British Journal of Haematology examines the use of venetoclax as a cytoreduction therapy for pediatric acute promyelocytic leukemia (APL). The study included 11 children with APL who were treated with arsenic and all-trans-retinoic acid (ATRA) in combination with either traditional cytoreduction therapy or venetoclax cytoreduction therapy. The patients treated with venetoclax had a higher rate of achieving hematological complete remission (HCR) on Day 28 of induction compared to those treated with traditional cytoreduction. Venetoclax also resulted in a lower incidence of differentiation syndrome (DS) and reduced reliance on platelet and plasma infusion. However, more research is needed to confirm these findings and evaluate the safety and effectiveness of venetoclax in this population. [Extracted from the article]

Summary: Aphid salivary proteins are critical in modulating plant defence responses. Grain aphid Sitobion miscanthi is an important wheat pest worldwide. However, the molecular basis for the regulation of the plant resistance to cereal aphids remains largely unknown. Here, we show that SmCSP4, a chemosensory protein from S. miscanthi saliva, is secreted into wheat plants during aphid feeding. Delivery of SmCSP4 into wheat leaves activates salicylic acid (SA)‐mediated plant defence responses and subsequently reduces aphid performance by deterring aphid feeding behaviour. In contrast, silencing SmCSP4 gene via nanocarrier‐mediated RNAi significantly decreases the ability of aphids to activate SA defence pathway. Protein–protein interaction assays showed that SmCSP4 directly interacts with wheat transcriptional factor TaWRKY76 in plant nucleus. Furthermore, TaWRKY76 directly binds to the promoter of SA degradation gene Downy Mildew Resistant 6 (DMR6) and regulates its gene expression as transcriptional activator. SmCSP4 secreted by aphids reduces the transcriptional activation activity of TaWRKY76 on DMR6 gene expression, which is proposed to result in increases of SA accumulation and enhanced plant immunity. This study demonstrated that SmCSP4 acts as salivary elicitor that is involved in activating SA signalling defence pathway of wheat by interacting with TaWRKY76, which provide novel insights into aphid‐cereal crops interactions and the molecular mechanism on induced plant immunity. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+/H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX‐induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX‐induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl‐2‐associated X protein/B‐cell lymphoma‐2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX‐induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: The immune system plays a pivotal role in the initiation, evolution, invasion and metastasis of cancer. Therapeutics aiming at modulating or boosting anticancer immune responses have experienced immense advances during the past decades, for example, anti‐PD‐1/PD‐L1 monoclonal antibodies. Main body: Concomitant with advancements in the understanding of novel mechanisms of action, conventional or emerging drugs bearing the potential to be repurposed for enhancing anticancer immunity have been identified. Meanwhile, ongoing advances in drug delivery systems enable us to utilise novel therapeutic strategies and impart drugs with fresh modes of action in tumour immunology. Conclusion: Herein, we systemically review these kinds of drugs and delivery systems that can unleash the anticancer response through various aspects, including immune recognition, activation, infiltration and tumour killing. We also discuss the current caveats and future directions of these emerging strategies. [ABSTRACT FROM AUTHOR]

Objective: Lenvatinib plus anti‐programmed death‐1 (anti‐PD‐1) antibody combinations have shown potent anti‐tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma (HCC), but real‐world data are limited. Methods: To investigate the effectiveness and safety of lenvatinib plus anti‐PD‐1 antibodies in a real‐world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022. Results: The objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression‐free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first‐line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child‐Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin–bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment‐related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%). Conclusion: Lenvatinib combined with anti‐PD‐1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child‐Pugh class B or ALBI grade 2/3. [ABSTRACT FROM AUTHOR]

The chemical diversity and structural flexibility of lead halide perovskites (LHPs) offer tremendous opportunities to tune their optical properties through internal molecular engineering and external stimuli. Herein, we report the wide‐range and ultrapure photoluminescence emissions in a family of homologous 2D LHPs, [MeOPEA]2PbBr4−4xI4x (MeOPEA=4‐methoxyphenethylammonium; x=0, 0.2, 0.425, 0.575, 1) enabled through internal chemical pressure and external hydrostatic pressure. The chemical pressure, induced by the C−H⋅⋅⋅π interactions and halogen doping/substitution strengthens the structural rigidity to give sustained narrow emissions, and regulates the emission energy, respectively. Further manipulation of physical pressure leads to wide‐range emission tuning from 412 to 647 nm in a continuous and reversible manner. This work could open up new pathways for developing 2D LHP emitters with ultra‐wide color gamut and high color purity which are highly useful for pressure sensing. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) represents an attractive promising route for melanoma treatment. However, its therapeutic efficacy is compromised by inefficient drug delivery and high glutathione (GSH) levels in cancer cells. To overcome these challenges, microneedles (MNs) system loaded with GSH-scavenging nanocomposites was presented for nitric oxide (NO) enhanced PDT. The nanocomposites consisted of S-nitroso-N-acrylate penicillamine (SNAP; a NO donor) grafted fourth-generation polyamide amine dendrimer (G4) and chlorin e6 (Ce6). Upon local insertion of polyvinylpyrrolidone MNs, G4-SNAP/Ce6 composites were fast delivered and significantly amplified the therapeutic effects during PDT, via GSH depletion and reactive nitrogen species generation. Even with a single administration and low power light exposure, MNs with G4-SNAP/Ce6 effectively halt the tumor progression. The system demonstrated better cancer ablation efficacy than Ce6 alone toward melanoma. The strategy may inspire new ideas for future PDT-related therapy for skin tumors. [ABSTRACT FROM AUTHOR]

Background: SQSTM1/p62 is a selective autophagy receptor that regulates multiple signaling pathways participating in the initiation and progression of tumors. Metastasis is still the main cause for intrahepatic cholangiocarcinoma (ICC)‐associated mortality. Hence, this study aimed to explore the mechanism of p62 promoting the progression of ICC. Methods: Western blotting and immunohistochemical analyses were conducted to detect the expression level of protein p62 in ICC tissues and its correlation with prognosis. Subsequently, the loss‐of‐function experiments in vitro and in vivo were performed to define the role of p62 in ICC cell proliferation, invasion, and metastasis. Then, the effect of p62 knockdown on mitochondrial function and mitophagy was evaluated by measuring the oxygen consumption rate, and using immunofluorescence and western blotting analyses. Results: The expression of p62 was significantly upregulated in ICC specimens compared with normal tissues. We further illustrated that p62 expression positively correlated with lymph node metastasis and poor prognosis. The loss‐of‐function assays revealed that p62 not only promoted ICC cell proliferation, migration, and invasive capacities in vitro, but also induced lung metastasis in the xenograft mouse model. Mechanistically, high expression of p62‐induced epithelial–mesenchymal transition (EMT) with the upregulation of Snail, vimentin, N‐cadherin, and downregulation of E‐cadherin. Moreover, the autophagy‐dependent function of p62 might play a vital role in maintaining the mitochondrial function of ICC by mitophagy which might further promote EMT. Conclusion: These data provided new evidence for the mechanism by which abundant p62 expression promoted ICC progression, suggesting a promising therapeutic target for antimetastatic strategies in patients with ICC. [ABSTRACT FROM AUTHOR]

Summary: Aphids secrete diverse repertoires of salivary effectors into host plant cells to promote infestation by modulating plant defence. The greenbug Schizaphis graminum is an important cereal aphid worldwide. However, the secreted effectors of S. graminum are still uncharacterized. Here, 76 salivary proteins were identified from the watery saliva of S. graminum using transcriptome and proteome analyses. Among them, a putative salivary effector Sg2204 was significantly up‐regulated during aphid feeding stages, and transient overexpression of Sg2204 in Nicotiana benthamiana inhibited cell death induced by BAX or INF1. Delivering Sg2204 into wheat via the type III secretion system of Pseudomonas fluorescens EtAnH suppressed pattern‐triggered immunity (PTI)‐associated callose deposition. The transcript levels of jasmonic acid (JA)‐ and salicylic acid (SA)‐associated defence genes of wheat were significantly down‐regulated, and the contents of both JA and SA were also significantly decreased after delivery of Sg2204 into wheat leaves. Additionally, feeding on wheat expressing Sg2204 significantly increased the weight and fecundity of S. graminum and promoted aphid phloem feeding. Sg2204 was efficiently silenced via spray‐based application of the nanocarrier‐mediated transdermal dsRNA delivery system. Moreover, Sg2204‐silenced aphids induced a stronger wheat defence response and resulted in negative impacts on aphid feeding behaviour, survival and fecundity. Silencing of Sg2204 homologues from four aphid species using nanocarrier‐delivered dsRNA also significantly reduced aphid performance on host plants. Thus, our study characterized the salivary effector Sg2204 of S. graminum involved in promoting host susceptibility by suppressing wheat defence, which can also be regarded as a promising RNAi target for aphid control. [ABSTRACT FROM AUTHOR]

The present study was conducted to determine the effects of the γ‐aminobutyric acid B (GABAB) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium‐pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P‐glycoprotein (P‐gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS‐1) and PI3K, as well as antiapoptotic factors (Bcl‐2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase‐3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM‐1, ICAM‐1, and tumor necrosis factor‐α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS‐1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS‐1/PI3K/Akt axis through crosstalk between GABAB and insulin‐like growth factor‐1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS‐1/PI3K/Akt axis, which may present a new therapeutic channel for RE. [ABSTRACT FROM AUTHOR]

Liver cancer is the fifth most common cancer and the second leading cause of malignant death in Asia, and Asia reports 72.5% of the world's cases in 2020. As the most common histological type, hepatocellular carcinoma (HCC) accounts for the majority of incidence and mortality of liver cancer cases. This review presents the changing epidemiology of HCC in Asian countries in recent years. Globally, aged, male and Asian populations remain the group with the highest risk of HCC. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are still the leading risk factors of HCC with a slight decline in most Asian countries, which is mainly attributed to HBV vaccination of newborns, prevention of HCV horizontal transmission and treatment of chronic hepatitis. However, the prevalence of HCC caused by metabolic factors, including metabolic syndrome, obesity and non‐alcoholic fatty liver diseases, is increasing rapidly in Asian countries, which may eventually become the major cause of HCC. Excessive alcohol consumption continues to be an important risk factor as the average consumption of alcohol is still growing. Hopefully, great effort has been made to better prevention and treatment of HCC in most Asian regions, which significantly prolongs the survival of HCC patients. Asian countries tend to use more aggressive intervention than European and American countries, but it remains unclear whether this preference is related to a better prognosis. In conclusion, HCC remains a major disease burden in Asia, and the management of HCC should be adjusted dynamically based on the changing epidemiology. [ABSTRACT FROM AUTHOR]

Immune-related pathways, such as chemokine signaling pathway, cytokine-cytokine receptor interaction, leukocyte transendothelial migration, antigen processing and presentation, as well as PD-L1 expression and PD-1 checkpoint pathway, were associated with GTs in various cancer types gl The pan-cancer GT-pathway interaction (Figure 2E to G and Supporting information Table S6) and GT-protein interaction networks (Supporting information Figures S8 to S10 and Table S7) were constructed, respectively. Dear Editor, Glycosyltransferases (GTs) played important roles in cancer development and progression.1,2 Here, we conducted a pan-cancer analysis of GTs (Supporting information Table S1)3 based on the TCGA data, CCLE data, single-cell RNA sequencing datasets and our proteogenomic resource, aiming to characterize the molecular features, biological functions and clinical implications of GTs across cancer types. GTs with mutation frequency >5% are highlighted as asterisks, and a total of 41 GTs had more than 5.0% of mutation frequencies across the pan-cancer cohort. In addition to LUAD and SKCM, GTs correlating with the prognosis of patients in CD8 SP + sp T cell-enriched tumors were observed in other 26 types of cancers (Supporting information Table S8). [Extracted from the article]

Pulmonary disease arising from slow‐growing mycobacterial infections has emerged as an increasingly prevalent clinical concern over the past two to three decades. Proteins belonging to the family of ESAT‐6 secretion (Esx) systems play critical roles in the virulence of most pathogenic mycobacterial species and are associated with drug resistance. However, no clinical applications can detect and discriminate the expression of species‐specific variants of these proteins in clinical samples, such as early growth cultures, for rapid diagnosis of specific mycobacterial infections, which may require distinct interventions. Conventional immunoassay approaches are not suitable for this purpose due to the significant degree of conservation of Esx proteins among species. Herein we describe the development of a novel immunoprecipitation‐coupled mass spectrometry assay that can distinguish Esx proteins that are expressed by slow‐growing mycobacterial species commonly detected in clinical isolates. This approach uses custom antibodies raised against single semi‐conserved peptide regions in M. tuberculosis (Mtb) EsxB and EsxN to capture corresponding peptides from protein orthologs of mycobacteria associated with human respiratory infections, including Mtb, M. avium, M. intracellulare, M. kansasii, M. gordonae, and M. marinum, to detect these species in standard clinical cultures at the first sign mycobacterial growth to allow rapid disease diagnosis. [ABSTRACT FROM AUTHOR]

Due to climate change, heat events in Canada have become more extreme in intensity and frequency and will continue to do so according to the Intergovernmental Panel on Climate Change's global predictions. Environmental justice research has indicated that extreme heat exposure disproportionally affects socio‐economically disadvantaged populations in cities. The objective of this research was to determine whether such a phenomenon exists in Montreal, Canada. Temperature data were obtained through in‐situ sensors and governmental weather stations, while census data were retrieved from Statistics Canada through the Census mapper. Correlation tests were run between temperature and five demographic and socio‐economic variables measured inside a 500 m buffer around the temperature sensors. The variables included Indigenous Peoples (IND), people of 65 years old and over (Over 65), people between 25 and 64 years old without a high school degree (No HS), and low‐income (LI). A positive correlation was found for LI and No HS (p < 0.05). A regression test performed with interpolated temperature and the demographic and socio‐economic variables across the study area revealed no significant correlation due to spatial heterogeneity. Key Messages: Low‐income individuals and those without a high school degree were affected by environmental injustice related to the urban heat island effect at the 500 m buffer level.Spatial heterogeneity across the Island of Montreal caused a lack of correlation between the remaining demographic and socio‐economic variables.Additional work is required to understand the contribution of urban social processes such as gentrification to the nature of this environmental injustice. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy with poor prognosis. As a cell adhesion molecule, poliovirus receptor (PVR/CD155) is abnormally overexpressed in tumour cells, and related to tumour proliferation and invasion. However, the potential role and mechanism of CD155 have not yet been elucidated in HCC. Methods: Immunohistochemistry, RT‐PCR and Western blot assays were used to determine CD155 expression in HCC cell lines and tissues. Cell Counting Kit‐8 and colony formation assays were used to examine cell proliferation. Transwell and wound healing assays were used to evaluate cell migration and invasion. Cell apoptosis and cycle distribution were assessed by flow cytometry. Cox regression and Kaplan–Meier analyses were performed to explore the clinical significance of CD155. The role of CD155 in vivo was evaluated by establishing liver orthotropic xenograft mice model. RNA sequencing, bioinformatics analysis and co‐immunoprecipitation assay were used to explore the downstream signalling pathway of CD155. Results: CD155 was upregulated in HCC tissues and represented a promising prognostic indicator for HCC patients (n = 189) undergoing curative resection. High CD155 expression enhanced cell proliferation, migration and invasion, and contributed to cell survival in HCC. CD155 overexpression also induced epithelial–mesenchymal transition in HCC cells. CD155 function in HCC involved SRC/p38 MAPK signalling pathway. CD155 interacted with SRC homology‐2 domain of SRC and promoted SRC activation, further inhibiting the downstream p38 MAPK signalling pathway in HCC. Conclusions: CD155 promotes HCC progression via the SRC/p38 MAPK signalling pathway. CD155 may represent a predictor for poor postsurgery prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

Objectives: We sought to evaluate the ability of the novel LA strain parameters to discriminate patients with heart failure with preserved ejection fraction (HFpEF) from individuals with risk factors of HFpEF. Methods and results: A total of n = 389 patients with risk factors for HFpEF finally was prospectively enrolled into the study, 66 of them were diagnosed with HFpEF by the 2021 ESC HF guidelines. Fifty‐five patients were undergone left ventricular catheterization and simultaneous transthoracic echocardiography was performed, 35 of them with elevated left ventricular end‐diastolic pressure (LVEDP). Left atrial reservoir strain (LASr) was measured in all patients. LA filling index was defined as the ratio of mitral E and LASr and LA stiffness index was calculated as E/e′/LASr. Compared with the patients in the normal LVEDP subgroup, those in the elevated LVEDP subgroup showed significantly higher LA filling index, LA stiffness index, and LAVI/LASr. The receiver‐operating characteristic curve (ROC) analysis showed LASr (area under curve [AUC].840), LA filling index (AUC.843), LA stiffness index (AUC.766), and LAVI/LASr (AUC.755) had good diagnostic accuracy for elevated LVEDP. Inter‐technique agreement analysis showed the novel algorithms with LA strain parameters had good agreement with the invasive LVEDP measurement, better than the 2016 ASE/SCAI algorithms (kappa.711 vs..101). Furthermore, compared with patients without HFpEF, LASr was lower in HFpEF, LA filling index, LA stiffness index, and LAVI/LASr was higher in patients with HFpEF. ROC analysis showed the novel LA strain parameters with good accuracy (AUC.756 to.821) non‐inferior to conventional echocardiographic parameters could identify HFpEF, and LA stiffness index (AUC.821) was the best one. Conclusion: The novel LA strain parameters could be of potential usefulness in estimating LVEDP and incorporated into the 2016 EACVI/ASE criteria would improve the diagnostic efficiency. The novel LA strain parameters with good accuracy non‐inferior to conventional echocardiographic parameters could discriminate HFpEF from patients with risk factors of HFpEF. [ABSTRACT FROM AUTHOR]

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC. [ABSTRACT FROM AUTHOR]

The idea that tumour microenvironment (TME) is organised in a spatial manner will not surprise many cancer biologists; however, systematically capturing spatial architecture of TME is still not possible until recent decade. The past five years have witnessed a boom in the research of high‐throughput spatial techniques and algorithms to delineate TME at an unprecedented level. Here, we review the technological progress of spatial omics and how advanced computation methods boost multi‐modal spatial data analysis. Then, we discussed the potential clinical translations of spatial omics research in precision oncology, and proposed a transfer of spatial ecological principles to cancer biology in spatial data interpretation. So far, spatial omics is placing us in the golden age of spatial cancer research. Further development and application of spatial omics may lead to a comprehensive decoding of the TME ecosystem and bring the current spatiotemporal molecular medical research into an entirely new paradigm. [ABSTRACT FROM AUTHOR]

Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single‐cell molecular analysis is required. We developed the ChimeraX®‐i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX®‐i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX®‐i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC‐positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single‐cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX®‐i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting. [ABSTRACT FROM AUTHOR]

BACKGROUND With the development of rapid resistance, new modes of action for pesticides are needed for insect control, such as RNAi‐based biopesticides targeting essential genes. To explore the function of Argonaute‐1 (Ago‐1) and potential miRNAs in ovarian development of Bactrocera dorsalis, an important agricultural pest, and to develop a novel control strategy for the pest, BdAgo‐1 was first identified in B. dorsalis. RESULTS: Spatiotemporal expression analysis indicated that BdAgo‐1 had a relatively high transcriptional level in the ovarian tissues of adult female B. dorsalis during the sexual maturation period. RNA interference (RNAi) experiment showed that BdAgo‐1 knockdown significantly decreased the expression levels of ovarian development‐related genes and delayed ovarian development. Although RNAi‐mediated silencing of Ago‐1 led to a reduced ovary surface area, a subsequent oviposition assay revealed that the influence was minimal over a longer time period. Small RNA libraries were constructed and sequenced from different ovarian developmental stages of B. dorsalis adults. Among 161 identified miRNAs, 84 miRNAs were differentially expressed during the three developmental stages of the B. dorsalis ovary. BdAgo‐1 silencing caused significant down‐regulation of seven differentially expressed miRNAs (DEMs) showing relatively high expression levels (>1000 TPM (Transcripts per kilobase of exon model per million mapped reads)). The expression patterns of these seven core DEMs and their putative target genes were analyzed in the ovaries of B. dorsalis. CONCLUSION: The results indicate that Ago‐1 and Ago‐1‐dependent miRNAs are indispensable for normal ovarian development in B. dorsalis and help identify miRNA targets useful for control of this pest. [ABSTRACT FROM AUTHOR]

Xiyanping (XYP) is a Chinese herbal medicine used in the clinic to treat respiratory infection and pneumonia. Recent evidence identified XYP as a potential inhibitor of severe acute respiratory syndrome coronavirus 2, implying XYP as a possible treatment for the coronavirus disease 2019 (COVID‐19). Here, we conducted a prospective, multicenter, open‐label and randomized controlled trial to evaluate the safety and effectiveness of XYP injection in patients with mild to moderate COVID‐19. We consecutively recruited 130 COVID‐19 patients with mild to moderate symptoms from five study sites, and randomized them in 1:1 ratio to receive XYP injection in combination with standard therapy or receive standard supportive therapy alone. We found that XYP injection significantly reduced the time to cough relief, fever resolution and virus clearance. Less patients receiving XYP injection experienced disease progression to the severe stage during the treatment process. No severe adverse events were reported during the study. Taken together, XYP injection is safe and effective in improving the recovery of patients with mild to moderate COVID‐19. However, further studies are warranted to evaluate the efficacy of XYP in an expanded cohort comprising COVID‐19 patients at different disease stages. [ABSTRACT FROM AUTHOR]

BACKGROUND: Odorant‐binding proteins (OBPs) in insects contribute to the sensitivity of the olfactory system and connect external odorants to olfactory receptor neurons. Determination of the chemosensory functions in Diaphorina citri, a vector of the citrus Huanglongbing pathogen, may help in developing a potential target for pest management. RESULTS: Diaphorina citri showed dose‐dependent electroantennogram recording (EAG) responses to 12 host plant volatiles. A two‐choice behavioral trap experiment showed that four compounds (methyl salicylate, linalool, citral and R‐(+)‐limonene) that elicited high EAG responses also had significant attraction to adults. The expression profiles induced by these compounds were detected in nine OBP genes, DcitOBP1–9. DcitOBP3, DcitOBP6 and DcitOBP7 commonly showed significant upregulation or downregulation compared with the control. Microscale thermophoresis (MST) showed that the recombinant protein DcitOBP7 had high in vitro binding affinities (Kd < 10 μm) to methyl salicylate, linalool and R‐(+)‐limonene, and moderate binding affinity to citral with a Kd value of 15.95 μm. Furthermore, RNA interference (RNAi)‐suppressed messenger RNA (mRNA) expression of DcitOBP7 resulted in a significant reduction in EAG activity and in adult D. citri behavioral responses to tested volatiles and the preferred host, Murraya paniculata. The hydrophilic residue Arg107 of DcitOBP7 may have a key role in binding odorants via formation of hydrogen bonds. CONCLUSION: These results show that DcitOBP7 plays an important role in the olfactory response. This finding may provide new insight into the functions of OBP families in D. citri and aid in the development of safe strategies for managing D. citri populations. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV‐related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. Methods: We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan‐Meier analysis and log‐rank test to identify lncRNA CNV with prognostic value. We conducted loss‐ and gain‐of‐function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR‐seq), quantitative real‐time PCR (qRT‐PCR), western blot, and dual‐luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull‐down, RNA immunoprecipitation, qRT‐PCR, and western blot analyses. Results: Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR‐199a‐5p, resulting in enhanced expression of SNAI1, which induced epithelial‐to‐mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. Conclusions: LINC01133 promotes HCC progression by sponging miR‐199a‐5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC. [ABSTRACT FROM AUTHOR]

Spatiotemporal molecular medicine aims to emphasize the importance of integrating multi-dimensional aspects of clinical medicine and molecular medicine - "a four-dimensional and dynamical picture of the disease by integrating clinical spatialization, temporalization, phenome, and molecular multi-omics for disease diagnosis, therapy, and prognosis".1 From an anatomical point, the "four-dimensional" aspects were proposed to be the length, width, and height, with time of organ/tissue development in physiological and pathophysiological conditions. Asp et al offered an approach to establish a database of heart spatial transcriptomics which can be further perfected in the future.5 The establishment of organ-wide orchestration of gene expression will be the initial and important step to facilitate spatiotemporal molecular pathology and imaging. Asp et al demonstrated a strategy to map the comprehensive transcriptional landscape of cell types in the embryonic heart at three developmental stages and defined cell-type-specific gene expression profiles in anatomical regions of certain levels in the heart.5 This provides clear evidence that the three-dimensional gene expression profiles and organ atlas can be generated along with organ anatomic architecture named "organ-wide orchestration of gene expression.". [Extracted from the article]

Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid‐specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p‐ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p‐ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara‐C)–resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara‐C treatment in both primary p‐ALL cells and pre‐B‐ALL–driven leukemia xenografts and prolonged the survival of tumor‐bearing mice. These data highlight an interconnected network of BACH2‐FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara‐C resistance in p‐ALL. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver transplantation (LTx) is one of the most effective treatments for hepatocellular carcinoma (HCC); however, tumour recurrence after LTx often leads to poor outcomes. This study investigated the value of circulating tumour cells (CTCs) as a predictor of recurrence following LTx in patients with HCC. Methods: This analysis included 193 patients with HCC who underwent LTx at our institute and accepted pre‐ and post‐operative CTC detection; 38 were selected for serial CTC monitoring. The predictive value of CTCs for tumour recurrence in patients with HCC following LTx was evaluated. Single‐cell whole genome sequencing was used to characterize CTCs. Results: Overall, the CTC burden decreased after LTx (P <.05). Post‐operative CTC count ≥ 1 per 5 mL peripheral blood was identified as a potential biomarker for predicting tumour recurrence after LTx, especially in patients with no detectable CTCs prior to LTx and negative tumour serological biomarkers. The predictive value of post‐operative CTC count ≥ 1 per 5 mL blood was retained in patients who did not meet the Milan criteria, University of California San Francisco (UCSF) criteria, or Fudan criteria (all P <.05). Furthermore, post‐operative serial CTC detection may be useful in post‐surgical surveillance for HCC recurrence. Conclusions: CTCs may be a useful biomarker to evaluate recurrence risk following LTx in patients with HCC. Evaluation based on CTC detection may enhance the post‐transplant management of HCC, and improve the therapeutic efficacy of LTx. [ABSTRACT FROM AUTHOR]

Spatiotemporal molecular medicine is a new discipline of medicine to precisely understand the pathogenesis, history, and epidemiology, and aims to achieve prevention, diagnosis, and therapy at molecular levels for human diseases in multidimensional aspects related to a spatial and temporal context. In comparison, spatiotemporal molecular medicine presents a four-dimensional and dynamical picture of the disease by integrating clinical spatialization, temporalization, phenome, and molecular multi-omics for disease diagnosis, therapy, and prognosis. For example, transcriptomic profiles of tissues, isolated single category of cells, or single cells demonstrate tissue- or cell-specific transcriptional function as one-dimensional information of mRNA expression. Lee et al. measured genomic and expression signatures of bulk cells, single cells, and selected regional cells isolated from tumor tissues and found the therapeutic response of glioma cells depended upon genetic similarity, mutations, and heterogeneities.8 Spatiotemporal molecular medicine could provide multidimensional insights into organogenesis during which gene regulations, protein interactions, and cell-cell communications in special positions are dynamically monitored for understanding mechanisms and prediction of diseases. [Extracted from the article]

Objective: To compare the clinical outcomes of horizontal mattress suture vs free‐edge suture in the all‐inside arthroscopic Broström–Gould procedure. Methods: This retrospective cohort study included 68 chronic lateral ankle instability (CLAI) patients who underwent either a horizontal mattress suture or a free‐edge suture all‐inside arthroscopic Broström–Gould procedure from January 2014 to January 2017. Patients were divided into two groups based on the suture fashion during the all‐inside arthroscopic Broström–Gould procedure. In the horizontal mattress suture group (n = 31), anchor sutures were used to suture the ATFL, capsule, and inferior extensor retinaculum in horizontal mattress suture fashion. In the free‐edge suture group (n = 37), anchor sutures were used to suture the ATFL, capsule, and inferior extensor retinaculum in free‐edge suture fashion. The Visual Analogue Scale (VAS) score, the American Orthopaedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Anterior Talar Translation (ATT), the rate of return to sports, and ankle proprioceptive recovery were compared in both groups. Results: The operative times and duration of hospitalization between the two groups were comparable (all P > 0.05). The VAS, AOFAS, ATT, the rate of return to sports, and ankle proprioceptive recovery were comparable between the horizontal mattress suture and free‐edge suture groups at 1 and 2 years after surgery. Patients of the free‐edge suture group achieved better KAFS 1 and 2 years after the surgery compared with those of the horizontal mattress suture group. In both groups, incisions were healed by first intention, and complications such as infection, implant reactions, tendon injury, and nervous or vascular injuries were not observed. The ankle proprioceptive recovery in horizontal mattress suture and free‐edge suture groups showed no significant differences at 1 and 2 years after surgery. The mean time of the return to full activity for patients in the horizontal mattress suture group was 10.38 ± 2.02 (range 8 to 12) weeks vs 8.63 ± 2.31 (range 8 to 12) weeks for those in the free‐edge suture group (P = 0.001, power = 0.907). The exercise participation rates were comparable between groups (P > 0.05). At the 2‐year follow‐up, all patients regained normal activities and ankle stability, and no recurrence of CLAI or revision surgery was recorded. Conclusion: All‐inside arthroscopic Broström–Gould surgery for the treatment of CLAI ensures a better functional effect (KAFS) and better recovery time when free‐edge suture is used instead of horizontal mattress suture. [ABSTRACT FROM AUTHOR]

Dear Editor, Though cancer immune therapy has achieved benefits in partial patients' population, the overall responses remain low, and low immune infiltration status has been deemed as a key factor leading to low response.1 In hepatocellular carcinoma (HCC), we found that tumor intrinsic oncogenic pathways were related to tumor infiltrating immune cells: mutation of I catenin beta 1 i I (CTNNB1) i or activation of the canonical I b-catenin i pathway was related to poor immune infiltration, while high expression of I Kirsten rat sarcoma viral oncogene homolog (KRAS) i was related to a better immune infiltration status, which provides new thoughts on combining immune therapy by targeting tumor intrinsic pathways and gives new markers for preference of treating methods. The protein expression of I KRAS i in HCC tissues was seen in only 37% of patients, while I CTNNB1 i was highly expressed, which may explain the immune suppressive microenvironment in liver tumor. [Extracted from the article]

The primary cilium is a sensory organelle that receives specific signals from the extracellular environment important for vertebrate development and tissue homeostasis. Lamins, the major components of the nuclear lamina, are required to maintain the nuclear structure and are involved in most nuclear activities. In this study, we show that deficiency in lamin A/C causes defective ciliogenesis, accompanied by increased cytoplasmic accumulation of actin monomers and increased formation of actin filaments. Disruption of actin filaments by cytochalasin D rescues the defective ciliogenesis in lamin A/C‐depleted cells. Moreover, lamin A/C‐deficient cells display lower levels of nesprin 2 and defects in recruiting Arp2, myosin Va, and tau tubulin kinase 2 to the basal body during ciliogenesis. Collectively, our results uncover a functional link between nuclear lamina integrity and ciliogenesis and implicate the malfunction of primary cilia in the pathogenesis of laminopathy. Synopsis: Lamin A, a major component of the nuclear lamina, regulates ciliogenesis through maintaining actin homeostasis. These findings indicate that defects in primary cilia may be involved in the pathogenesis of laminopathies, such as Hutchinson‐Gilford progeria syndrome. Lamin A‐deficient cells, including fibroblasts derived from Hutchinson‐Gilford progeria syndrome patients, lamin A/C-depleted RPE cells, and tissues from Lmna−/− mice, display decreased cilia incidence and cilia length.In lamin A‐, nesprin 2‐ or importin 9‐deficient cells, defective ciliogenesis is accompanied by increased formation of actin filaments. Disruption of the actin filaments by cytochalasin D rescues ciliogenesis.Nuclear lamina integrity is important for recruiting Arp2 and myosin Va to the basal body during ciliogenesis. [ABSTRACT FROM AUTHOR]

A new structure named reinforced concrete grid moment‐resisting frame (RC‐GMRF) have been adopted in high‐rise buildings in China. However, complex construction due to numerous beam‐column joints restricts the application of this structure. A novel precast reinforced concrete GMRF (PC‐GMRF) is proposed in this paper to solve this problem. Three specimens, including one traditional reinforced concrete moment‐resisting frame (RC‐MRF) as reference, were tested under reverse cyclic loading to evaluate the seismic performance. All three specimens were designed using the same amount of construction material. The experimental results showed that PC‐GMRF exhibited comparable seismic performance with that of RC‐GMRF. The load‐carrying capacity, initial stiffness and energy dissipation capacity were improved by an average of 43%, 29%, and 21%, respectively, compared with those of RC‐MRF. This study indicated that the performance of PC‐GMRF was acceptable and could be used in the moment‐resisting frame as a novel structure. [ABSTRACT FROM AUTHOR]

Background: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. Methods: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. Results: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P <.001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P <.001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α‐fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α‐fetoprotein level during postoperative follow‐up (all P <.05). The results were confirmed in the validation cohort. Conclusions: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM. A postoperative circulating tumor cell (CTC) count ≥3 is a surrogate marker for the prediction of extrahepatic metastases after curative surgical resection of hepatocellular carcinoma. A more careful surveillance of metastatic spread should be recommended to patients with a high CTC load after hepatectomy. [ABSTRACT FROM AUTHOR]