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Background: Early recurrence is the leading cause of death for patients with perihilar cholangiocarcinoma (pCCA) after surgery. Identifying high-risk patients preoperatively is important. This study aimed to construct a preoperative prediction model for the early recurrence of patients with pCCA to facilitate planned treatment with curative resection., Methods: This study ultimately enrolled 400 patients with pCCA after curative resection in 5 hospitals between 2013 and 2019. They were randomly divided into training (n = 300) and testing groups (n = 100) at a ratio of 3:1. Associated variables were identified via least absolute shrinkage and selection operator (LASSO) regression. Four machine learning models were constructed: support vector machine, random forest (RF), logistic regression, and K-nearest neighbors. The predictive ability of the models was evaluated via receiving operating characteristic (ROC) curves, precision-recall curve (PRC) curves, and decision curve analysis. Kaplan-Meier (K-M) survival curves were drawn for the high-/low-risk population., Results: Five factors: carbohydrate antigen 19-9, tumor size, total bilirubin, hepatic artery invasion, and portal vein invasion, were selected by LASSO regression. In both the training and testing groups, the ROC curve (area under the curve: 0.983 vs 0.952) and the PRC (0.981 vs 0.939) showed that RF was the best. The cutoff value for distinguishing high- and low-risk patients was 0.51. K-M survival curves revealed that in both groups, there was a significant difference in RFS between high- and low-risk patients (P < .001)., Conclusion: This study used preoperative variables from a large, multicenter database to construct a machine learning model that could effectively predict the early recurrence of pCCA in patients to facilitate planned treatment with curative resection and help clinicians make better treatment decisions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m 2 ), normal BMI (18.5-24.9 kg/m 2 ), and high BMI (≥25.0 kg/m 2 ). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

Background: Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion., Methods: The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma., Results: We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient's imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma., Conclusions: Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion., (© 2024. The Author(s).)

Background: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively., Methods: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared., Results: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups., Conclusions: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Using a quinoline substituted Qsal ligand, Hqsal-5-Br q (Hqsal-5-Br q = N-(5-bromo-8-quinolyl)salicylaldimine), four Fe III complexes, [Fe(qsal-5-Br q ) 2 ]A·CH 3 OH (Y = NO 3 - ( 1 NO3 ), BF 4 - ( 2 BF4 ), PF 6 - ( 3 PF6 ), OTf - ( 4 OTf ), were prepared and characterized. Structure analysis revealed that complex 2 BF4 contained two species ( 2 BF4 ( P 1 ̅) and 2 BF4 ( C 2/ c )). In these compounds except 3 PF6 , the [Fe(qsal-5-Br q ) 2 ] + cations form 1D chains through π-π interactions and other weak interactions. Adjacent chains are connected to form the 2D "Chain Layer" structures and 3D structures through various supramolecular interactions. For 3 PF6 , a "Dimer Chain" structure is formed from the loosely connected dimers. Magnetic studies revealed that compounds 1 NO3 and 2 BF4 ( P 1 ̅) displayed abrupt hysteretic SCO with the transition temperature T 1/2 ↓ = 235 K, T 1/2 ↑ = 240 K for 1 NO3 and T 1/2 ↓ = 230 K, T 1/2 ↑ = 235 K for 2 BF4 ( P 1̅ ), while compounds 3 PF6 and 4 OTf are in the HS state. Desolvation of the complexes significantly modifies their SCO properties: the desolvated 1 NO3 and 2 BF4 show a gradual SCO, desolvated 3 PF6 undergoes a two-step SCO, and desolvated 4 OTf exhibits a hysteretic transition. Overall, this work reported the Fe III -SCO complexes of the quinoline-substituted Hqsal ligand and highlighted the potential of these ligands for the development of interesting Fe III -SCO materials.

Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers., (©2023 American Association for Cancer Research.)

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals., Competing Interests: Competing interests M.G. is founder, consultant, member of the board and equity holder in Forcefield Therapeutics, Heqet Therapeutics and Purespring Therapeutics. All other authors declare no competing interests.

Wastewater discharge from outfall pipes can significantly impact river water quality and aquatic ecosystems. Effective outfall monitoring is critical for controlling pollution and protecting public health. This study demonstrates a novel distributed acoustic sensing (DAS) approach for detecting wastewater discharge events from outfall pipes located along rivers. Controlled field experiments were conducted in an industrial park river to systematically evaluate DAS performance. DAS detects vibrational signals imparted to suspended fiber-optic cables by turbulent wastewater flows, predominantly within 10-30 Hz, enabling continuous monitoring along entire river lengths. Vibrational power analysis locates outfalls with meter-level accuracy, while time-frequency techniques discern discharge timing and characteristics. Cable type and outfall-fiber separation influence on detection capability was assessed. Thermoplastic-jacketed tight buffer cables optimized detection through enhanced vibrational coupling. Vibrational energy decreased exponentially with separation, highlighting benefits of proximal deployment for sensitivity. However, detection range scales with discharge flow rate. Frequency centroid proved a robust feature with potential for automated discharge identification. Overall, DAS enables high spatiotemporal resolution monitoring to pinpoint concealed outfalls minimally invasively. This positions DAS as a promising tool supporting improved water governance through early pollution warnings and rapid source localization via outfall vibrational signatures emanating across river networks., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cheng-Cheng Zhang, Bin Shi reports financial support was provided by National Natural Science Foundation of China. Cheng-Cheng Zhang reports financial support was provided by China Association for Science and Technology., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Three new cyano-bridged Fe II -Mo III complexes assembled from the [Mo III (CN) 7 ] 4- unit, Fe II ions, and three pentadentate N 3 O 2 ligands, namely {[Fe 2 H 3 (dapab) 2 ][Mo(CN) 6 ]} n ·2H 2 O·3.5MeCN ( 1 ), [Fe(H 2 dapb)(H 2 O)][Fe(Hdapb)(H 2 O)][Mo(CN) 6 ]·4H 2 O·3MeCN ( 2 ), and [Fe(H 2 dapba)(H 2 O)] 2 [Mo(CN) 7 ]·6H 2 O ( 3 ) (H 2 dapab = 2,6-diacetylpyridine bis(2-aminobenzoylhydrazone), H 2 dapb = 2,6-diacetylpyridine bis(benzoylhydrazone), H 2 dapba = 2,6-diacetylpyridine bis(4-aminobenzoylhydrazone)), have been synthesized and characterized. Single-crystal structure analyses suggest that complex 1 contains a one-dimensional (1D) chain structure where two Fe II ions are bridged by the in situ generated [Mo III (CN) 6 ] 3- unit through two trans -cyanide groups into trinuclear Fe 2 II Mo III clusters that are further linked by the amino of the ligand into an infinite chain. Complexes 2 and 3 are cyano-bridged Fe 2 II Mo III trinuclear clusters with two Fe II ions connected by the [Mo III (CN) 6 ] 3- and [Mo III (CN) 7 ] 4- units, respectively. Direct current magnetic studies confirmed the ferromagnetic interactions between the cyano-bridged Fe II and Mo III centers and significant easy-axis magnetic anisotropy for all three complexes. Furthermore, complexes 1-3 exhibit slow magnetic relaxation under a zero dc field, with relaxation barriers of 42.3, 21.6, and 14.4 K, respectively, making them the first examples of cyano-bridged Fe II -Mo III single-molecule magnets.

A novel bis-bidentate nitronyl nitroxide radical based on triazolopyrimidine, NIT-2-TrzPm (NIT-2-TrzPm = (2-(2'-triazolopyrimidine)-4,4,5,5-tetramethyl-4,5-dihydro-1 H -imidazol-1-oxy-3-oxide)) and six new transition metal complexes of this ligand, namely [M(hfac) 2 (NIT-2-TrzPm)]·CH 2 Cl 2 (M = Mn (1Mn) and Co (2Co)), [M(hfac) 2 ] 2 (NIT-2-TrzPm) (M = Mn (3Mn) and Co (4Co)), [Mn(NIT-2-TrzPm) 2 (MeOH) 2 ](ClO 4 ) 2 ·MeOH (5Mn), and [Co(NIT-2-TrzPm) 2 (MeOH) 2 ] 2 (ClO 4 ) 4 ·4MeOH (6Co) were prepared and characterized structurally and magnetically. These complexes can be selectively synthesized by controlling the reaction ratio of M(hfac) 2 ·2H 2 O to the radical ligand (for 1Mn to 4Co) or using metal perchlorates as the starting materials (for 5Mn and 6Co). Single crystal X-ray crystallographic analyses confirmed that 1Mn and 2Co are isostructural 3d-2p M II -radical complexes, in which the NIT-2-TrzPm radical acts as a terminal bidentate ligand chelating to one 3d ion, while 3Mn and 4Co are isostructural 3d-2p-3d M II -radical-M II complexes with the NIT-2-TrzPm radical acting as a bridging ligand between two 3d ions. For complexes 5Mn and 6Co, two NIT-2-TrzPm ligands from the equatorial positions coordinate with the metal center to form the 2p-3d-2p structures with the axial positions occupied by two methanol molecules. Magnetic analysis on the Mn II complexes revealed the existence of a strong antiferromagnetic interaction between the Mn II and the NIT radical spin, while weak ferromagnetic coupling for Mn⋯Mn and Rad⋯Rad in the Mn-NIT-Mn and Rad-Mn-Rad spins was confirmed. Interestingly, although the NIT-bridged complexes 3Mn and 4Co possess significantly different magnetic anisotropy, field-induced slow magnetic relaxation can be observed in both complexes, which was assigned to the phonon bottleneck effect for 3Mn and field-induced SMM behavior for 4Co. To the best of our knowledge, 3Mn is the first example of the NIT-bridged binuclear Mn II complex undergoing slow magnetic relaxation.

Objective: The study aimed to analyze the current status and reasons for the neglect of the psychological need of patients with common skin diseases., Methods: This cross-sectional study was conducted in China using an online self-assessment questionnaire distributed via social media. Demographic, clinical and psychological data were collected, and the main outcomes, i.e., depression (evaluated using the 9-item Patient Health Questionnaire, PHQ-9) and anxiety (evaluated using Generalized Anxiety Disorder-7, GAD-7). Multivariate regression analysis was used for the prediction of variates of mental health service seeking behaviors., Results: A total of 1,010 patients participated in the survey, and 273 (27.0%) patients met the "with need" criteria, i.e., having the need for mental health intervention but not being treated. In the multivariate regression model, income (OR = 0.80, 95%CI: 0.65-0.99), duration of disease (OR = 0.68, 95%CI: 0.49-0.95) and suicide ideation (OR = 2.10, 95%CI: 1.14-3.87) were significant factors. For patients who did not receive mental health care, the lack of knowledge about the availability of mental health services, lack of knowledge of where to seek help, concerns about the side effects of treatment, failure to seek treatment for severe skin diseases, and absence of current psychological distress were associated with their need for psychological intervention., Conclusion: This study examined the current status of the need for psychological intervention and the reasons why the need was unmet in patients with skin diseases. Due to the confusion and a lack of knowledge about their mental health issues, mental health services are often underutilized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Wang, Li, Yang, Zhang, Lin, Ke, Zhang, Su and Zhu.)

Background: The hepatic artery is the only blood source nourishing the biliary duct and associated with biliary complication after liver transplantation (LT). Gastroduodenal artery (GDA) disconnection increased proper hepatic artery flow. Whether this procedure attenuates biliary non-anastomotic stricture (NAS) is not clear., Methods: A total of 241 patients with LT were retrospectively analyzed. The patients were divided into the GDA disconnection (GDA-) and GDA preservation (GDA+) groups. Propensity score matching (PSM) was administrated to reduce bias. Logistic regression was conducted to analyze risk factors for biliary NAS before and after PSM. Postoperative complications were compared. Kaplan-Meier survival analysis and log-rank tests were performed to compare overall survival., Results: In all, 99 patients (41.1%) underwent GDA disconnection, and 49 (20.3%) developed NAS. Multivariate logistic regression revealed that GDA preservation (OR = 2.24, 95% CI: 1.11-4.53; P = 0.025) and model for end-stage liver disease (MELD) score > 15 (OR = 2.14, 95% CI: 1.12-4.11; P = 0.022) were risk factors for biliary NAS. PSM provided 66 pairs using 1:2 matching method, including 66 GDA disconnection and 99 GDA preservation patients. Multivariate logistic regression after PSM also showed that GDA preservation (OR = 3.15, 95% CI: 1.26-7.89; P = 0.014) and MELD score > 15 (OR = 2.41, 95% CI: 1.08-5.36; P = 0.031) were risk factors for NAS. When comparing complications between the two groups, GDA preservation was associated with a higher incidence of biliary NAS before and after PSM (P = 0.031 and 0.017, respectively). In contrast, other complications including early allograft dysfunction (P = 0.620), small-for-size graft syndrome (P = 0.441), abdominal hemorrhage (P = 1.000), major complications (Clavien-Dindo grade ≥ 3, P = 0.318), and overall survival (P = 0.088) were not significantly different between the two groups., Conclusions: GDA disconnection during LT ameliorates biliary NAS incidence and may be recommended for application in clinical practice., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients., Areas Covered: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials., Expert Opinion: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

Immunosuppressive myeloid cells in the tumor microenvironment inhibit anti-tumor immunity and support tumor development. The leukocyte Ig-like receptor subfamily B (LILRB) proteins and the related receptor LAIR1 are immune checkpoint receptors that support the immunosuppressive activity of myeloid cells. All LILRBs and LAIR1 have intracellular immunoreceptor tyrosine-based inhibitory motifs in their signaling domains, but the individual proteins have different functions. The determinants of the distinct functions of these inhibitory receptors likely rest in their interactions with different ligands and other surface proteins, characteristic signaling domains, and expression dynamics in different cell types regulated by various extrinsic cues and transcription factors. Significant advancement of immuno-oncology therapeutic products based on targeting or reprogramming of LILRB- and LAIR1-mediated signaling is anticipated., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Depressive disorder is the leading cause of disability worldwide, yet the mechanisms underlying depression are not fully understood. Vesicle release is essential for synaptic neurotransmission, the abnormalities of vesicle release and synaptic plasticity are associated with various neuropsychiatric disorders. Neural circuits are ensembles of interconnected neurons that collectively perform specific functions. To some extent, depression may be caused by a disruption in the structural and functional connections of the neural circuits underlying emotion regulation. In this review, we summarized the role of abnormalities of vesicle release and synaptic transmission, as well as the related regulatory molecules and signal pathways in the regulation of depression., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: As one of the most common stroke sequelae, poststroke cognitive impairment significantly impacts 17.6%-83% of survivors, affecting their rehabilitation, daily living and quality of life. Improving cognitive abilities among patients in stroke recovery is therefore critical and urgent. Transcutaneous auricular vagus nerve stimulation (TAVNS) is a non-invasive, safe, cost-effective treatment with great potential for improving the cognitive function of poststroke patients. This clinical research will evaluate the effectiveness, and help elucidate the possible underlying mechanisms, of TAVNS for improving poststroke cognitive function., Methods and Analysis: A single-centre, parallel-group, allocation concealment, assessor-blinded randomised controlled clinical trial. We will allocate 88 recruited participants to the TAVNS or sham group for an intervention that will run for 8 weeks, 5 days per week with twice daily sessions lasting 30 min each. Blood tests will be performed and questionnaires issued at baseline and 8-week and 12 week follow-ups. Primary outcomes will be changes in cognitive function scores. Secondary outcomes will be changes in activities of daily living, quality of life and serum oxidative stress indicators., Ethics and Dissemination: The Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine has approved the protocol (No. HN-LL-YJSLW-2022200). Findings will be published in peer-reviewed academic journals and presented at scientific conferences., Trial Registration Number: ChiCTR2200057808., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The current immune checkpoint blockade therapy has been successful in treating some cancers but not others. New molecular targets and therapeutic approaches of cancer immunology need to be identified. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) is an immune inhibitory receptor expressing on most immune cell types. However, it remains a question whether we can specifically and actively block LAIR1 signaling to activate immune responses for cancer treatment. Here we report the development of specific antagonistic anti-LAIR1 monoclonal antibodies and studied the effects of LAIR1 blockade on the anti-tumor immune functions. The anti-LAIR1 antagonistic antibody stimulated the activities of T cells, natural killer cells, macrophages, and dendritic cells in vitro . The single-cell RNA sequencing analysis of intratumoral immune cells in syngeneic human LAIR1 transgenic mice treated with control or anti-LAIR1 antagonist antibodies indicates that LAIR1 signaling blockade increased the numbers of CD4 memory T cells and inflammatory macrophages, but decreased those of pro-tumor macrophages, regulatory T cells, and plasmacytoid dendritic cells. Importantly, the LAIR1 blockade by the antagonistic antibody inhibited the activity of immunosuppressive myeloid cells and reactivated T cells from cancer patients in vitro and impeded tumor metastasis in a humanized mouse model. Blocking LAIR1 signaling in immune cells represents a promising strategy for development of anti-cancer immunotherapy., Competing Interests: JJX, XG, XCL, NZ, ZA, CCZ, and XCL were inventors of a patent application covering anti-LAIR1 antibodies and their uses. NZ, ZA, and CCZ hold equity in and have Sponsored Research Agreements with Immune-Onc Therapeutics, Inc. XCL and TH are employees and hold equities of Immune-Onc Therapeutics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Gui, Deng, Chen, Chen, Liu, Ku, Tan, Huang, He, Zhang, Lewis, Chen, Xu, Xu, Huang, Liao, Zhang, An and Zhang.)

Four iron(III) complexes, [Fe(qsal-4-F) 2 ]Y·sol (Hqsal-4-F = 4-fluoro- N -(8-quinolyl)salicylaldimine; Y = NO 3 - , sol = 0.91MeOH·0.57H 2 O ( 1 NO3 ); Y = PF 6 - ( 2 PF6 ); Y = BF 4 - ( 3 BF4 ); Y = OTf - , sol =1.5MeOH ( 4 OTf )), with a new 4-position substituted qsal type ligand Hqsal-4-F have been synthesized and structurally and magnetically characterized. Complexes 1 NO3 - 3 BF4 consist of 1D chains formed by the [Fe(qsal-4-F) 2 ] + cations connected by π-π and C-H···O interactions, which are further linked by more weak interactions to form 2D layers and 3D networks. On the other hand, complex 4 OTf has a structure of nearly isolated 1D column where the [Fe(qsal-4-F) 2 ] + cations are connected by π-π, C-H···π, and C-F···π interactions. Magnetic studies revealed the occurrence of two-step symmetry-breaking SCO in 1 NO3 and two-step gradual SCO in 2 PF6 . Complex 3 BF4 undergoes a gradual SCO, whereas 4 OTf remains almost high-spin. The smaller anions tend to stabilize the low-spin state, while larger anions tend to stabilize the high-spin state. In addition, the intermediate spin state of 1 NO3 could be thermally trapped by quenching from the high temperature, thereby kinetically suppressing the spin transition to the full low-spin state. This work represents a good example that the position of the substituent and the anions plays critical roles in the preparation of SCO materials with tunable properties.

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER + ) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER + breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER + breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants., (© 2022. The Author(s).)

Objective: Several lines of evidence demonstrated the role of anesthetic drugs in cognitive functions. Some anesthetic agents have been confirmed to be associated with long-term spatial memory and learning in aged animal models., Methods: C57BL/6 mice were divided into four different groups based on different concentrations of remimazolam treatments. Behavioral phenotype was observed by open field, rota rod, Morris water maze, and elevated plus maze test. Western blot was performed to see the expression pattern of different proteins. Confocal microscopy images were taken for neuronal and glial cells to see the effect of remimazolam on CNS cells., Results: We showed that remimazolam, a new anesthetic drug, impaired cognitive behavior. Repetitive doses of remimazolam have been found to induce neuronal loss with a significant change in morphology. Here, we showed that a higher concentration of remimazolam had a significant effect on CNS cell activation. We showed that remimazolam caused memory dysfunction by inducing neuronal apoptosis via glutamate excitotoxicity. It also exhibited amyloid β plaque in the brain via abnormal phosphorylation of tau protein. Remimazolam-mediated regulation of glial cells in mouse cortex was observed and robust activation of astrocytes and microglial cells was found. Finally, we assessed the behavioral phenotype of mice and found that treatment with remimazolam induced significant behavioral changes and memory dysfunction., Conclusions: This study provides insight into the mechanism of anesthetic drug-induced memory deficits and may help improve the therapeutic effects of anesthesia agents in clinical applications., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2022 Xin-hua Zhou et al., published by De Gruyter.)

Background: Bone transport has been successfully applied for the management of large segmental bone defects. However, its main shortcoming is the long-lasting consolidation period, which may cause lots of related complications. To overcome this shortcoming, we developed bone transport combined with bone graft and internal fixation technique. The purpose of this study was to compare the clinical effects of this modified technique with simple bone transport in the treatment of large segmental bone defects of lower limbs after trauma., Methods: Eighty-four patients with large segmental bone defects treated in our institution from January 2014 to January 2017 were selected for retrospective study. A total of 77 cases were completely followed. Among them, 35 patients were treated by bone transport combined with bone graft and internal fixation technique (Group A), and 42 by simple bone transport technique (Group B). Patients with open injuries were classified according to Gustilo-Anderson (GA) classification. The general data of Group A and B were compared. The time in external fixator, total cure time and operation times of two groups were recorded. Ennecking score was used to evaluate the recovery of limb functions while self-rating anxiety scale (SAS) for the postoperative anxiety evaluation. In addition, the total complication incidence was compared between Group A and B., Results: There was no significant difference in demographic data between Group A and B (p > 0.05). The time in external fixator of Group A and B was (4.8 ± 1.6) and (18.2 ± 3.9) months, respectively (p < 0.05). The total cure time was (17.6 ± 2.2) and (20.4 ± 2.8) months in Group A and B (p < 0.05). The number of operations in Group A and B was (4.9 ± 1.2) and (4.8 ± 1.0) (p > 0.05). Ennecking score of Group A and B was 84.7 and 75.7% (p < 0.05). SAS score and total complication incidence in Group A were significantly lower than those in Group B (p < 0.05)., Conclusions: The clinical effects of bone transport combined with bone graft and internal fixation technique were better than that of simple bone transport technique, including shorter time in external fixator, shorter total cure time, lower anxiety score and better limb functions., (© 2022. The Author(s).)

Objective: We present the first case of prenatally diagnosed isochromosome 4p with whole 4q arm translocating to chromosome 9p23 and review the literature., Case Report: A 26-year-old woman underwent amniocentesis at 25 weeks of gestation because of an abnormal ultrasound examination. Routine chromosome analysis on cultured amniocytes showed a karyotype of 46,XX, ?idic(4)(q11),der(9)t(4;9)(q11;p23). Single nucleotide polymorphism (SNP) array analysis on uncultured amniocytes detected two copy number variations (CNVs): arr [GRCh37] 4p16.3p11(68345-49089361) × 3; arr [GRCh37] 9p24.3p23(208454-10039391) × 1. The karyotypes of the parents were normal, indicating that the chromosomal rearrangement was de novo. According to the fetal-parent trios SNP analysis, both the abnormal chromosomes were originated from the father. The pregnancy was terminated at 30 weeks of gestation, and a malformed fetus was delivered with dysmorphic craniofacial, short neck, wide-spaced nipples and rocker-bottom feet., Conclusion: The combined application of traditional cytogenetic technology and molecular diagnosis technology in prenatal diagnosis helps identify genetic components and the origin of isochromosome, which enable clinicians to precisely predict the fetal prognosis and provide accurate genetic counselling and fertility guidance., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

As a clean and renewable energy, bioenergy is one of the most promising alternatives to fossil fuels. Lignocellulose possesses great potential for bioenergy production, but the recalcitrant and heterogeneous structure limits its application. Pretreatment technology offers an effective solution to fractionate the main components of the lignocellulose and uncover the available cellulose. The obtained feedstock can be applied to bioconversion into energy, e.g., bioethanol, biogas, biohydrogen, etc. Here, the current state of lignocellulose pretreatment technologies was comprehensively reviewed, the advances in bioenergy production from pretreated lignocellulose was described, with particular attention to key challenges involved. Several new strategies for overcoming pretreatment barriers to realize highly efficient lignocellulose bioconversion were highlighted. The insights given in this review will facilitate further development on lignocellulosic bioenergy production, towards addressing the global energy crisis and climate change related to the use of fossil fuels., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: New B-cell markers are needed for monitoring B lymphoblastic leukemia (B-ALL) in the era of immunotherapies directed against CD19 and CD22. The expression of leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) on hematogones in bone marrow (BM) and neoplastic B lymphoblasts has not yet been systematically investigated., Methods: We assessed LILRB1 expression pattern on B cells in 19 control BMs and 22 B-ALL cases by flow cytometry., Results: In all cases, mature B cells and hematogones exhibited a consistent pattern of LILRB1 expression with variable intensity over different stages of maturation, including a characteristic V-shaped pattern on hematogones. While neoplastic B lymphoblasts in all cases expressed LILRB1, the pattern of expression was distinctly abnormal relative to hematogones (loss of the dynamic pattern in all cases and abnormal expression levels in 83% of cases)., Conclusions: LILRB1 is a novel diagnostic B-cell marker to aid in distinguishing neoplastic B lymphoblasts from hematogones., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2 +/- ) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2 +/- rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning., (© 2021. The Author(s).)

Background: Preoperative serum carbohydrate antigen 125 (CA125) is used to judge the diagnosis and prognosis of various tumors. However, the relationship between preoperative serum CA125 and prognosis of hilar cholangiocarcinoma (HCCA) has not been proven. This study aims to evaluate preoperative serum CA125 in predicting the prognosis of HCCA after resection., Methods: A total of 233 patients after radical resection of HCCA were included. The associations between the levels of preoperative serum CA125 and the clinicopathological characteristics of patients were analyzed. Survival curves were calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression models were used to identify independent risk factors associated with recurrence-free survival (RFS) and overall survival (OS)., Results: Among 233 patients, 198 (84.97%) with normal CA125 levels (≤35 U/mL) had better OS and RFS than 35 (15.02%) patients with higher CA125 levels (>35 U/mL). Preoperative serum CA125 was significantly correlated with tumor size, Bismuth-Corlette classification, microvascular invasion and carcinoembryonic antigen (CEA) (p < 0.001, p = 0.040, p = 0.019 and p = 0.042, respectively). The results of multivariable Cox regression showed that preoperative serum CA125 >35 U/mL (p = 0.002, HR = 1.910 for OS; p = 0.006, HR = 1.755 for RFS), tumor classification (p < 0.001, HR = 2.110 for OS; p = 0.006, HR = 1.730 for RFS), lymph node metastasis (p < 0.001, HR = 1.795 for OS; p < 0.001, HR = 1.842 for RFS) and major vascular invasion (p = 0.002, HR = 1.639 for OS; p = 0.005, HR = 1.547 for RFS) were independent risk factors for both OS and RFS., Conclusions: Preoperative serum CA125 is a good tumor marker for predicting prognosis after radical surgery for HCCA., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Leukocyte immunoglobulin-like receptor B (LILRB), a family of immune checkpoint receptors, contributes to acute myeloid leukemia (AML) development, but the specific mechanisms triggered by activation or inhibition of these immune checkpoints in cancer is largely unknown. Here we demonstrate that the intracellular domain of LILRB3 is constitutively associated with the adaptor protein TRAF2. Activated LILRB3 in AML cells leads to recruitment of cFLIP and subsequent NF-κB upregulation, resulting in enhanced leukemic cell survival and inhibition of T-cell-mediated anti-tumor activity. Hyperactivation of NF-κB induces a negative regulatory feedback loop mediated by A20, which disrupts the interaction of LILRB3 and TRAF2; consequently the SHP-1/2-mediated inhibitory activity of LILRB3 becomes dominant. Finally, we show that blockade of LILRB3 signaling with antagonizing antibodies hampers AML progression. LILRB3 thus exerts context-dependent activating and inhibitory functions, and targeting LILRB3 may become a potential therapeutic strategy for AML treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Ultrasonic surface deep rolling (USDR), oxygen boost diffusion (OBD), and their combination (USDR-OBD) were all used to improve the surface hardening of pure titanium. The microstructure, microhardness, and fatigue life of pure titanium treated by USDR, OBD, and USDR-OBD methods were analyzed. USDR treatment induced a severe deformation area, while OBD treatment produced a brittle oxygen diffusion zone. The USDR-OBD treated samples approached the highest hardness in comparison with other treated samples. The fatigue lives of USDR treated samples were improved, which was due to the high compressive residual stress and refined grains. However, the fatigue lives of both OBD treated samples and USDR-OBD treated samples were decreased due to premature crack initiation and rapid propagation in the oxygen diffusion zone. Finally, the fatigue fracture mechanisms of different samples were proposed., (© 2021. The Author(s).)

Background: Acute myeloid leukemia (AML) with monocytic differentiation (M-AML) remains a diagnostic challenge largely due to lack of sensitive and specific markers for immature monocytes. The immunoglobulin-like inhibitory receptors, LILRB1 and LILRB4, are expressed on monocytes but have not yet been systematically evaluated in the clinical setting., Methods: We evaluated the diagnostic performance of LILRB1 and LILRB4 as monocytic markers for both immature and mature monocytes in comparison to other myelomonocytic markers including CD14, CD15, CD33, CD36, and CD64 in eight cases of control bone marrow (BM, 5) and peripheral blood (PB, 3), 64 cases of (M-AML), and 57 cases of AML without monocytic differentiation (NM-AML) by flow cytometric immunophenotyping., Results: In control BM, LILRB1 and LILRB4 were consistently expressed on monocytes at all stages of maturation, from CD34 + /CD14 - monocytic precursors to CD14 -/dim+ maturing and CD14 + mature monocytes. In M-AML, LILRB1 and LILRB4 were consistently expressed on monocytes, regardless of the degree of maturity, from CD14 -/dim+ monoblasts/promonocytes to CD14 + mature monocytes but were not expressed on myeloblasts. The diagnostic performances as a monocytic marker assessed by sensitivity/specificity were 100%/100% for LILRB1/LILRB4, 100%/82% for CD11b, 80%/100% for CD14, 100%/81% for CD64, 100%/58% for CD15/CD33, and 89%/97% for CD36/CD64., Conclusion: The co-expression of LILRB1/LILRB4 outperformed other myelomonocytic markers as a highly sensitive and specific marker for monocytes at all stages of maturation and could reliably distinguish M-AML from NM-AML. LILRB4 additionally represents a novel therapeutic target for treating M-AML., (© 2020 International Clinical Cytometry Society.)

Transposable elements or transposons are major players in genetic variability and genome evolution. Aberrant activation of long interspersed element-1 (LINE-1 or L1) retrotransposons is common in human cancers, yet their tumor-type-specific functions are poorly characterized. We identified MPHOSPH8/MPP8, a component of the human silencing hub (HUSH) complex, as an acute myeloid leukemia (AML)-selective dependency by epigenetic regulator-focused CRISPR screening. Although MPP8 is dispensable for steady-state hematopoiesis, MPP8 loss inhibits AML development by reactivating L1s to induce the DNA damage response and cell cycle exit. Activation of endogenous or ectopic L1s mimics the phenotype of MPP8 loss, whereas blocking retrotransposition abrogates MPP8-deficiency-induced phenotypes. Expression of AML oncogenic mutations promotes L1 suppression, and enhanced L1 silencing is associated with poor prognosis in human AML. Hence, while retrotransposons are commonly recognized for their cancer-promoting functions, we describe a tumor-suppressive role for L1 retrotransposons in myeloid leukemia.

Vertical deformation profiles of subterranean geological formations are conventionally measured by borehole extensometry. Distributed strain sensing (DSS) paired with fiber-optic cables installed in the ground opens up possibilities for acquiring high-resolution static and quasistatic strain profiles of deforming strata, but it is currently limited by reduced data quality due to complicated patterns of interaction between the buried cables and their surroundings, especially in upper soil layers under low confining pressures. Extending recent DSS studies, we present an improved approach using microanchored fiber-optic cables-designed to optimize ground-to-cable coupling at the near surface-for strain determination along entire lengths of vertical boreholes. We proposed a novel criterion for soil-cable coupling evaluation based on the geotechnical bearing capacity theory. We applied this enhanced methodology to monitor groundwater-related vertical motions in both laboratory and field experiments. Corroborating extensometer recordings, acquired simultaneously, validated fiber optically determined displacements, suggesting microanchored DSS as an improved means for detecting and monitoring shallow subsurface strain profiles.

Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1-5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs that recruit phosphatases to negatively regulate immune activation. The activation of LILRB signaling in immune cells may contribute to immune evasion. In addition, the expression and signaling of LILRBs in cancer cells especially in certain hematologic malignant cells directly support cancer development. Certain LILRBs thus have dual roles in cancer biology-as immune checkpoint molecules and tumor-supporting factors. Here, we review the expression, ligands, signaling, and functions of LILRBs, as well as therapeutic development targeting them. LILRBs may represent attractive targets for cancer treatment, and antagonizing LILRB signaling may prove to be effective anti-cancer strategies., (© The Author(s) 2021. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19)., Methods: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively., Results: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients., Conclusions: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5320). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML) varies, ranging from 0.6%-46%. Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be critical in orchestration of infiltration of AML cells into the CNS in animal models, however it is unknown if an association exists between LILRB4 and CNS involvement (CNS+) in human patients with AML. LILRB4 was measured by flow cytometry in a heterogeneous population of fifty-six AML patients. Patients were then followed clinically for the development of CNS + . LILRB4 was positive in 91 % of patients with CNS + compared to 38 % without CNS involvement (p < 0.002). In logistic analysis: age, BMI, serum albumin and positive LILRB4 were predictive for CNS+ [OR, 95 % CI, p-value]: 0.95, 0.92-0.99, p < 0.01; 0.85, 0.73-0.998, p < 0.05; 0.23, 0.066-0.78, p < 0.02; 16.46, 1.93-140.2, p < 0.02, respectively. This finding of the association of LILRB4 with CNS + in combination with earlier findings suggests that LILRB4 has a mechanistic role in infiltration of the CNS and may provide insight into the pathogenesis of AML seeding the CNS. Moreover, this proof of concept and the findings in the present study may lead to the development of innovative and novel therapies to improve the lives of patients with AML., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Body mass index (BMI) has been widely used as a prognostic indicator. The association between preoperative BMI and postoperative morbidity in patients with hilar cholangiocarcinoma (HCCA) has not been proved. This study aimed to identify the association between preoperative BMI and postoperative morbidity following radical resection of HCCA., Methods: Patients were divided into three groups according to preoperative BMI: low BMI (≤18.4 kg/m 2 ), normal BMI (18.4-24.9 kg/m 2 ), and high BMI (≥24.9 kg/m 2 ). Baseline characteristics, operative variables, postoperative 30-day mortality, and morbidity were compared. Risk factors associated with postoperative morbidity were assessed using univariable and multivariable logistic analyses., Results: Among 260 patients, 183 (70.4%) had normal BMI, 32 (12.3%) had low BMI, and 45 (17.3%) had high BMI. Compared to the patients with normal-BMI, both low and high BMI patients exhibited a significantly higher postoperative morbidity (87.5% and 82.2% vs 63.9%, P = .019 and P = .025, respectively). Additionally, the multivariable analysis revealed that both low and high BMI patients remained independently associated with an increased risk of postoperative morbidity. (OR: 3.707, 95% CI: 1.080-12.725, P = .037; and OR: 2.858, 95% CI: 1.167-7.002, P = .022, respectively)., Conclusion: BMI is an independent risk factor for higher postoperative morbidity in patients who undergo surgical treatment of hilar cholangiocarcinoma., (© 2020 Wiley Periodicals LLC.)

Background: Iatrogenic biliary injury (IBI) following laparoscopic cholecystectomy (LC) is the most serious iatrogenic complications. Little is known whether LC-IBI would lead to surgeon's severe mental distress (SMD)., Methods: A cross-sectional survey in the form of electronic questionnaire was conducted among Chinese general surgeons who have caused LC-IBI. The six collected clinical features relating to mental distress included: 1) feeling burnout, anxiety, or depression, 2) avoiding performing LC, 3) having physical reactions when recalling the incidence, 4) having the urge to quit surgery, 5) taking psychiatric medications, and 6) seeking professional psychological counseling. Univariable and multivariable analyses were performed to identify risk factors of SMD, which was defined as meeting ≥3 of the above-mentioned clinical features., Results: Among 1466 surveyed surgeons, 1236 (84.3%) experienced mental distress following LC-IBI, and nearly half (49.7%, 614/1236) had SMD. Multivariable analyses demonstrated that surgeons from non-university affiliated hospitals (OR:1.873), patients who required multiple repair operations (OR:4.075), patients who required hepaticojejunostomy/partial hepatectomy (OR:1.859), existing lawsuit litigation (OR:10.491), existing violent doctor-patient conflicts (OR:4.995), needing surgeons' personal compensation (OR:2.531), and additional administrative punishment by hospitals (OR:2.324) were independent risk factors of surgeon's SMD., Conclusion: Four out of five surgeons experienced mental distress following LC-IBI, and nearly half had SMD. Several independent risk factors of SMD were identified, which could help to make strategies to improve surgeons' mental well-being., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody-drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin (Mylotarg). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 mAb and the antimitotic payload, monomethyl auristatin F. The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerted a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of anti-LILRB4 ADCs in monocytic AML therapy., (©2020 American Association for Cancer Research.)

Background: A normal albumin-to-globulin ratio (NAGR) in serum is greater than 1. Inversed albumin-to-globulin ratio (IAGR < 1) indicates poor synthetic liver function or malnutrition. The aim of this study is to evaluate whether preoperative IAGR was associated with worse oncologic survival after hepatectomy for hepatocellular carcinoma (HCC)., Patients and Methods: Patients who underwent curative hepatectomy for HCC between 2009 and 2016 in four centers were divided into the IAGR and NAGR groups based on their preoperative levels, and their clinical characteristics and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors of overall survival (OS) and recurrence-free survival (RFS)., Results: Of 693 enrolled patients, 136 (19.6%) were in the IAGR group. Their 5-year OS and RFS rates were 31.6% and 21.3%, respectively, which were significantly worse than the NAGR group (43.4% and 28.7%, both P < 0.001). The area under the receiver operating characteristic curves in predicting 5-year OS and RFS using the albumin-to-globulin ratio were 0.68 and 0.67, respectively, which were significantly higher than albumin (0.60 and 0.59), globulin (0.56 and 0.57), Child-Pugh grading (0.61 and 0.60), Model for End-Stage Liver Disease Score (0.59 and 0.58), and Albumin-Bilirubin grading (0.64 and 0.63). Multivariable analyses identified that preoperative IAGR was independently associated with worse OS (HR: 1.444, 95% confidence interval (CI): 1.125-1.854, P = 0.004) and RFS (HR: 1.463, 95% CI: 1.159-1.848, P = 0.001)., Conclusion: Preoperative IAGR was useful in predicting worse OS and RFS in patients who underwent curative hepatectomy for HCC., Competing Interests: The authors report no conflicts of interest for this work., (© 2020 Zhang et al.)

Background: Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment., Methods: First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice., Results: We demonstrate that percentage of LILRB1 + NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1 + NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo ., Conclusions: Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy., Competing Interests: Competing interests: ZA, and CCZ. are Scientific Advisory Board members with Immune-Onc Therapeutics. A.K. is an advisory Board member of BMS, Takeda, Pfizer, Janssen, Sanofi, Karyopharm and GSK. ZA, and CCZ, NZ, MD, XG, and JK hold equity in Immune-Onc Therapeutics. ZA, CCZ, NZ, HC, YC are inventors of LILRB1-related patent., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Anxiety disorder is a common mental health disorder. However, there are few safe and fast-acting anxiolytic drugs available that can treat anxiety disorder. We previously demonstrated that the interaction of neuronal NOS (nNOS) with its carboxy-terminal PDZ ligand (CAPON) is involved in regulating anxiety-related behaviours. Here, we further investigated the anxiolytic effects of nNOS-CAPON disruptors in chronic stress-induced anxiety in animals., Experimental Approach: Mice were intravenously treated with nNOS-CAPON disruptors, ZLc-002 or Tat-CAPON12C, at the last week of chronic mild stress (CMS) exposure. We also infused corticosterone (CORT) into the hippocampus of mice to model anxiety behaviours and also delivered ZLc-002 or Tat-CAPON12C on the last week of chronic CORT treatment via pre-implanted cannula. Anxiety-related behaviours were examined using elevated plus maze, open field, novelty-suppressed feeding and light-dark (LD) tests. The level of nNOS-CAPON interaction was determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). The neural mechanisms underlying the behavioural effects of nNOS-CAPON uncoupling in anxiety animal models were assessed by western blot, immunofluorescence and Golgi-Cox staining., Key Results: ZLc-002 and Tat-CAPON12C reversed CMS- or CORT-induced anxiety-related behaviours. ZLc-002 and Tat-CAPON12C increased synaptogenesis along with improved dendritic remodelling in CMS mice or CORT-treated cultured neurons. Meanwhile, blocking nNOS-CAPON interaction significantly activated the cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) pathway, which is associated with synaptic plasticity., Conclusion and Implications: Collectively, these results provide evidence for the anxiolytic effects of nNOS-CAPON uncouplers and their underlying mechanisms in anxiety disorders., (© 2020 The British Pharmacological Society.)

Hepatocellular carcinoma (HCC) is reported to associate with abnormal expression of SCF E3 ubiquitin ligases. FBXW10, an F-box protein of the E3 ubiquitin ligases, was abnormally regulated in HCC patients. However, whether FBXW10 is associated with HCC has not yet been evaluated. Here, we analyzed the associations between overall survival and various risk factors in 191 HCC tissues. Univariate and multivariate analyses demonstrated that FBXW10 was an independent risk factor related to HCC prognosis. The results showed that FBXW10, gender and tumor state were strongly associated with overall survival in HCC patients. Furthermore, high expression of FBXW10 was associated with poor survival among male HCC patients but not female HCC patients. FBXW10 was more highly expressed in male HCC tissues and more strongly related to vascular invasion in male HCC patients. Consistent with these findings, the male FBXW10-Tg(+) mice were more susceptible to tumorigenesis, changes in regenerative capacity, and liver injury and inflammation but not changes in liver function than FBXW10-Tg(-) mice. FBXW10 promoted cell proliferation and migration in HCC cell lines. Our findings reveal that FBXW10, an independent risk factor for HCC, promotes hepatocarcinogenesis in male patients, and is also a potential prognostic marker in male patients with HCC., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)