Deciphering lung granulomas in HIV & TB co-infection: unveiling macrophages aggregation with IL6R/STAT3 activation.

Tuberculosis (TB) remains a leading cause of mortality among individuals coinfected with HIV, characterized by progressive pulmonary inflammation. Despite TB's hallmark being focal granulomatous lung lesions, our understanding of the histopathological features and regulation of inflammation in HIV & TB coinfection remains incomplete. In this study, we aimed to elucidate these histopathological features through an immunohistochemistry analysis of HIV & TB co-infected and TB patients, revealing marked differences. Notably, HIV & TB granulomas exhibited aggregation of CD68 + macrophage (Mφ), while TB lesions predominantly featured aggregation of CD20+ B cells, highlighting distinct immune responses in coinfection. Spatial transcriptome profiling further elucidated CD68+ Mφ aggregation in HIV & TB, accompanied by activation of IL6 pathway, potentially exacerbating inflammation. Through multiplex immunostaining, we validated two granuloma types in HIV & TB versus three in TB, distinguished by cell architecture. Remarkably, in the two types of HIV & TB granulomas, CD68 + Mφ highly co-expressed IL6R/pSTAT3, contrasting TB granulomas' high IFNGRA/SOCS3 expression, indicating different signaling pathways at play. Thus, activation of IL6 pathway may intensify inflammation in HIV & TB-lungs, while SOCS3-enriched immune microenvironment suppresses IL6-induced over-inflammation in TB. These findings provide crucial insights into HIV & TB granuloma formation, shedding light on potential therapeutic targets, particularly for granulomatous pulmonary under HIV & TB co-infection. Our study emphasizes the importance of a comprehensive understanding of the immunopathogenesis of HIV & TB coinfection and suggests potential avenues for targeting IL6 signaling with SOCS3 activators or anti-IL6R agents to mitigate lung inflammation in HIV & TB coinfected individuals.

Development of GPC3-CAR-NK cells and optimization as a therapy for HCC.

Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by insidious onset and rapid progression, with limited treatment choices. One treatment modality, chimeric antigen receptor (CAR)-modified natural killer (NK) cell immunotherapy, has shown promise for various cancers. In this study, we developed two GPC3-specific CAR-NK-92 cell lines (GPC3-CAR-NK) and explored their antitumor efficacy for the treatment of HCC. Significant levels of cytokine production and in vitro cytotoxicity were produced following co-culture of GPC3+ HCC cells with the developed GPC3-CAR-NK cells. GC33-G2D-NK cells with NK cell-specific signaling domains showed better activation and killing abilities than GC33-CD28-NK cells containing T cell-specific signaling domains. Moreover, GC33-G2D-NK cells efficiently eliminated tumors in cell-derived xenograft and patient-derived xenograft mouse models. In an abdominal metastasis model, intraperitoneally delivered GC33-G2D-NK cells showed better antitumor ability than intravenously injected cells. Finally, the combination of microwave ablation with GC33-G2D-NK cell administration showed greater CAR-NK infiltration and tumor regression in ablated tumors than monotherapy alone. These findings indicate that administration of GPC3-CAR-NK cells may be a potential strategy for the treatment of HCC, and regional delivery or their combination with microwave ablation may optimize their efficacy against HCC and may have translational value.

Analysis of Replication, Cell Division-Mediated Spread, and HBV Envelope Protein-Dependent Pseudotyping of Three Mammalian Delta-like Agents.

The human hepatitis delta virus (HDV) is a satellite RNA virus that depends on hepatitis B virus (HBV) surface proteins (HBsAg) to assemble into infectious virions targeting the same organ (liver) as HBV. Until recently, the evolutionary origin of HDV remained largely unknown. The application of bioinformatics on whole sequence databases lead to discoveries of HDV-like agents (DLA) and shed light on HDV's evolution, expanding our understanding of HDV biology. DLA were identified in heterogeneous groups of vertebrates and invertebrates, highlighting that the evolution of HDV, represented by eight distinct genotypes, is broader and more complex than previously foreseen. In this study, we focused on the characterization of three mammalian DLA discovered in woodchuck (Marmota monax), white-tailed deer (Odocoileus virginianus), and lesser dog-like bat (Peropteryx macrotis) in terms of replication, cell-type permissiveness, and spreading pathways. We generated replication-competent constructs expressing 1.1-fold over-length antigenomic RNA of each DLA. Replication was initiated by transfecting the cDNAs into human (HuH7, HeLa, HEK293T, A549) and non-human (Vero E6, CHO, PaKi, LMH) cell lines. Upon transfection and replication establishment, none of the DLA expressed a large delta antigen. A cell division-mediated viral amplification assay demonstrated the capability of non-human DLA to replicate and propagate in hepatic and non-hepatic tissues, without the requirement of envelope proteins from a helper virus. Remarkably L-HDAg but not S-HDAg from HDV can artificially mediate envelopment of WoDV and DeDV ribonucleoproteins (RNPs) by HBsAg to form infectious particles, as demonstrated by co-transfection of HuH7 cells with the respective DLA expression constructs and a plasmid encoding HBV envelope proteins. These chimeric viruses are sensitive to HDV entry inhibitors and allow synchronized infections for comparative replication studies. Our results provide a more detailed understanding of the molecular biology, evolution, and virus-host interaction of this unique group of animal viroid-like agents in relation to HDV.

RP11-874 J12.4 promotes erlotinib resistance in non-small cell lung cancer via increasing AXL expression.

EGFR tyrosine kinase inhibitor (TKI) resistance is a major challenge for EGFR-mutant non-small cell lung cancer (NSCLC) treatment. Our previous work revealed that overexpression of AXL promoted EGFR-TKI resistance through epithelial-mesenchymal transition (EMT) in a subset of NSCLC patients. Compared with erlotinib resistant and sensitive cells, RP11-874 J12.4 was upregulated in erlotinib-resistant NSCLC cells (HCC827-ER3). Interestingly, the expression of RP11-874 J12.4 positively correlated with AXL. Besides, RP11-874 J12.4 promotes NSCLC cell proliferation and metastasis in vitro. Mechanistically, RP11-874 J12.4 promoted AXL expression through sponge with miR-34a-5p, which was reported to inhibit the translation of AXL mRNA. Meanwhile, the expression of RP11-874 J12.4 in lung cancer tumors were higher than the adjacent tissue, and those patients with high expression of RP11-874 J12.4 showed a poor prognosis in clinical. High expression of RP11-874 J12.4 might be a biomarker for NSCLC patients with erlotinib resistance. These findings reveal a novel insight into the mechanism of erlotinib resistance in NSCLC, and it might be a promising target for the diagnosis and treatment of NSCLC.

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer's disease: a Mendelian randomization study.

Background: Studies have reported that metabolic disturbance exhibits in patients with Alzheimer's disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention. Methods: We conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary two-sample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings. Results: After rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data. Conclusion: By integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD.

Silicon Vacancies Diamond/Silk/PVA Hierarchical Physical Unclonable Functions for Multi-Level Encryption.

Physical unclonable functions (PUFs) have emerged as a promising encryption technology, utilizing intrinsic physical identifiers that offer enhanced security and tamper resistance. Multi-level PUFs boost system complexity, thereby improving system reliability and fault tolerance. However, crosstalk-free multi-level PUFs remain a persistent challenge. In this study, a hierarchical PUF system that harnesses the spontaneous phase separation of silk fibroin /PVA blend and the random distribution of silicon-vacancy diamonds within the blend is presented. The thermodynamic instability of phase separation and inherent unpredictability of diamond dispersion gives rise to intricate random patterns at two distinct scales, enabling time-efficient hierarchical authentication for cryptographic keys. These patterns are complementary yet independent, inherently resistant to replication and damage thus affording robust security and reliability to the proposed system. Furthermore, customized authentication algorithms are constructed: visual PUFs authentication utilizes neural network combined structural similarity index measure, while spectral PUFs authentication employs Hamming distance and cross-correlation bit operation. This hierarchical PUF system attains a high recognition rate without interscale crosstalk. Additionally, the coding capacity is exponentially enhanced using M-ary encoding to reinforce multi-level encryption. Hierarchical PUFs hold significant potential for immediate application, offering unprecedented data protection and cryptographic key authentication capabilities.

The tibial capsular reflection and septum in posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in posterior cruciate ligament reconstruction.

PURPOSE: To investigate the validity of using tibial capsular reflection and septum in the posterior compartment as landmark during posterior cruciate ligament (PCL) reconstruction (PCLR). METHODS: Anatomic measurements were obtained for 12 fresh human cadaveric knee specimens to observe the spatial position of the tibial insertion of the PCL in relation to the posterior septum and the capsular reflection in the posterior compartment. Sixty patients who underwent reconstruction of the PCL between 2020 and 2023 were also retrospectively investigated. The tibial tunnel was replaced in all patients using the same method (with reference to the tibial capsular reflection and the posterior septum). The placement of the tibial tunnel was assessed using X-ray fluoroscopy intraoperatively and computed tomography and three-dimensional reconstruction postoperatively. RESULTS: All fibres in the tibial insertion of the PCL in the 12 cadaveric specimens were located in the posteromedial compartment, adjacent to the posterior septum. The inferior border of the PCL insertion is adjacent to the tibial capsular reflection, which is attached at the champagne glass drop-off of the posterior tibia. In our previous cases, none of the patients experienced postoperative or intraoperative complications such as neurovascular injury, and the angle between the pin and the PCL facet was 93.1 ± 3.9° as measured on intraoperative radiographs. The mean distance from the centre of the tibial tunnel outlet to the inferior border of the PCL insertion was 5.6 ± 1.1 mm, and the distance from the centre of the tibial tunnel outlet to the outer border of the PCL insertion as a percentage of the length of the inferior border of PCL insertion was 42.2 ± 6.3%. CONCLUSION: The tibial capsular reflection and septum in the posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in PCLR. LEVEL OF EVIDENCE: Level Ⅳ.

Interface Modulation for the Heterointegration of Diamond on Si.

Along with the increasing integration density and decreased feature size of current semiconductor technology, heterointegration of the Si-based devices with diamond has acted as a promising strategy to relieve the existing heat dissipation problem. As one of the heterointegration methods, the microwave plasma chemical vapor deposition (MPCVD) method is utilized to synthesize large-scale diamond films on a Si substrate, while distinct structures appear at the Si-diamond interface. Investigation of the formation mechanisms and modulation strategies of the interface is crucial to optimize the heat dissipation behaviors. By taking advantage of electron microscopy, the formation of the epitaxial ß-SiC interlayer is found to be caused by the interaction between the anisotropically sputtered Si and the deposited amorphous carbon. Compared with the randomly oriented ß-SiC interlayer, larger diamond grain sizes can be obtained on the epitaxial ß-SiC interlayer under the same synthesis condition. Moreover, due to the competitive interfacial reactions, the epitaxial ß-SiC interlayer thickness can be reduced by increasing the CH4/H2 ratio (from 3% to 10%), while further increase in the ratio (to 20%) can lead to the broken of the epitaxial relationship. The above findings are expected to provide interfacial design strategies for multiple large-scale diamond applications.

CAR-NK cells in combination therapy against cancer: A potential paradigm.

Various preclinical and a limited number of clinical studies of CAR-NK cells have shown promising results: efficient elimination of target cells without side effects similar to CAR-T therapy. However, the homing and infiltration abilities of CAR-NK cells are poor due to the inhibitory tumor microenvironment. From the perspective of clinical treatment strategies, combined with the biological and tumor microenvironment characteristics of NK cells, CAR-NK combination therapy strategies with anti-PD-1/PD-L1, radiotherapy and chemotherapy, kinase inhibitors, proteasome inhibitors, STING agonist, oncolytic virus, photothermal therapy, can greatly promote the proliferation, migration and cytotoxicity of the NK cells. In this review, we will summarize the targets selection, structure constructions and combinational therapies of CAR-NK cells for tumors to provide feasible combination strategies for overcoming the inhibitory tumor microenvironment and improving the efficacy of CAR-NK cells.

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer.

Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

Solar-Blind Photodetector Arrays Fabricated by Weaving Strategy.

The quest for solar-blind photodetectors (SBPDs) with exceptional optoelectronic properties for imaging applications has prompted the investigation of SBPD arrays. Ga2O3, characterized by its ultrawide bandgap and low growth cost, has emerged as a promising material for solar-blind detection. In this study, SBPD arrays were fabricated by weaving Sn-doped ß-Ga2O3 microbelts (MBs). These MBs, which have a conductive core surrounded by a high-resistivity depletion surface layer resulting from the segregation of Sn and oxygen, are woven into a grid structure. Each intersection of the MBs functions as a photodetector pixel, with the intersecting MBs serving as the output electrodes of the pixel. This design simplifies the readout circuit for the photodetector array. The solar-blind photodetector array demonstrates superior solar-blind detection performance, including a dark current of 0.5 pA, a response time of 38.8 µs, a light/dark current ratio of 108, and a responsivity of 300 A/W. This research may provide a feasible strategy for the fabrication of photodetector arrays, thus pushing forward the application of photodetectors in imaging.

Anatomical Observation and Clinical Significance of the Medial Branch of the Lumbar Dorsal Rami.

STUDY DESIGN: Anatomical study. OBJECTIVE: This study aimed to elaborate on the anatomical characteristics of the medial branch of the lumbar dorsal rami and to discuss its possible clinical significance. SUMMARY OF BACKGROUND DATA: Radiofrequency ablation targeting the medial branch of the lumbar dorsal rami has been increasingly used in the clinical management of facetogenic low back pain (FLBP). Nonetheless, attention is also being given to complications such as atrophy of the lumbar soft tissues and muscles. Therefore, a more detailed understanding of the innervation pattern on the facet joint may improve the precision of nerve ablation therapy for FLBP. METHODS: An anatomical study of eight human specimens was carried out. The anatomic characteristics of the medial branch were observed and recorded. RESULTS: The medial branch originates from the lumbar dorsal rami, running close to the root of the posterolateral side of the superior articular process of the inferior cone. When passed through the mamillo-accessory ligament, it turns direction to the medial and caudal side, running in the multifidus muscle. In our study, each medial branch sent out two to five branches along the way. All the medial branches in L1-L4 gave off one to two small branches when crossing the facet joint and innervated the joint of the lower segment. Nineteen medial branches (23.75%) gave off recurrent branches to innervate the joint at the upper segment. CONCLUSION: The anatomical features of the medial branch remain similar in each lumbar segment. There are two types of joint branches, including the articular fibers that emanate from the medial branch as it runs along the medial border of the facet joint and the recurrent branch from the medial branch that innervates the upper facet joint. Moreover, an anastomotic branch was found in the medial branches between different segments.

A modified anatomical posterior cruciate ligament reconstruction technique using the posterior septum and posterior capsule as landmarks to position the low tibial tunnel.

BACKGROUND: Lowering the exit position of the tibial tunnel can improve the clinical efficacy of posterior cruciate ligament (PCL) reconstruction, however, there is no unified positioning standard. This study aimed to use novel soft tissue landmarks to create a low tunnel. METHODS: A total of 14 human cadaveric knees and 12 patients with PCL injury were included in this study. Firstly, we observed the anatomical position between the PCL, posterior septum, and other tissue, and evaluated the relationship between the center of the low tibial tunnel (SP tunnel) and posterior septum and distal reflection of posterior capsule, and using computed tomography (CT) to evaluate distance between the center of the SP tunnel with bony landmarks. Then, evaluated the blood vessels content in the posterior septum with HE staining. Finally, observed the posterior septum and distal reflection of the posterior capsule under arthroscopy to explore the clinical feasibility of creating a low tibial tunnel, and assessed the risk of surgery by using ultrasound to detect the distance between the popliteal artery and the posterior edge of tibial plateau bone cortex. RESULTS: In all 14 cadaveric specimens, the PCL tibial insertions were located completely within the posterior medial compartment of the knee. The distance between the center of the SP tunnel and the the articular surface of tibial plateau was 9.4 ± 0.4 mm. All SP tunnels retained an intact posterior wall, which was 1.6 ± 0.3 mm from the distal reflection of the posterior capsule. The distances between the center of the SP tunnel and the the articular surface of tibial plateau, the champagne glass drop-off were 9.2 ± 0.4 mm (ICC: 0.932, 95%CI 0.806-0.978) and 1.5 ± 0.2 mm (ICC:0.925, 95%CI 0.788-0.975) in CT image. Compared with the posterior capsule, the posterior septum contained more vascular structures. Last, all 12 patients successfully established low tibial tunnels under arthroscopy, and the distance between the posterior edge of tibial plateau bone cortex and the popliteal artery was 7.8 ± 0.3, 9.4 ± 0.4 and 7.4 ± 0.3 mm at 30°, 60° and 90° flexion angels after filling with water and supporting with shaver in posterior-medial compartment of knee joint. CONCLUSIONS: A modified low tibial tunnel could be established in the PCL anatomical footprint by using the posterior septum and posterior capsule as landmarks.

Cobalt-Catalyzed Enantioselective Reductive Amination of Ketones with Hydrazides.

An efficient cobalt-catalyzed asymmetric reductive amination of ketones with hydrazides has been realized, directly producing valuable chiral hydrazines in high yields and enantioselectivities (up to 98% enantiomeric excess).

Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy.

Survivin is a novel attractive target for cancer therapy; however, it is considered undruggable because it lacks enzymatic activities. Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110. Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cells A549 with an IC50 value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells. Further biological studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy. Furthermore, the promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by the overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (KD = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.

Hepatitis D infection induces IFN-ß-mediated NK cell activation and TRAIL-dependent cytotoxicity.

Background and aims: The co-infection of hepatitis B (HBV) patients with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis and thus drastically worsens the course of the disease. Therapy options for HBV/HDV patients are still limited. Here, we investigated the potential of natural killer (NK) cells that are crucial drivers of the innate immune response against viruses to target HDV-infected hepatocytes. Methods: We established in vitro co-culture models using HDV-infected hepatoma cell lines and human peripheral blood NK cells. We determined NK cell activation by flow cytometry, transcriptome analysis, bead-based cytokine immunoassays, and NK cell-mediated effects on T cells by flow cytometry. We validated the mechanisms using CRISPR/Cas9-mediated gene deletions. Moreover, we assessed the frequencies and phenotype of NK cells in peripheral blood of HBV and HDV superinfected patients. Results: Upon co-culture with HDV-infected hepatic cell lines, NK cells upregulated activation markers, interferon-stimulated genes (ISGs) including the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), produced interferon (IFN)-γ and eliminated HDV-infected cells via the TRAIL-TRAIL-R2 axis. We identified IFN-ß released by HDV-infected cells as an important enhancer of NK cell activity. In line with our in vitro data, we observed activation of peripheral blood NK cells from HBV/HDV co-infected, but not HBV mono-infected patients. Conclusion: Our data demonstrate NK cell activation in HDV infection and their potential to eliminate HDV-infected hepatoma cells via the TRAIL/TRAIL-R2 axis which implies a high relevance of NK cells for the design of novel anti-viral therapies.

Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer.

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3'-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.

Cobalt-Catalyzed Efficient Asymmetric Hydrogenation of α-Primary Amino Ketones.

Based on an amino-group-assisted coordination strategy and a proton-shuttle-activated outer-sphere mode, the cobalt-catalyzed asymmetric hydrogenation of α-primary amino ketones has been developed, resulting in the efficient synthesis of chiral vicinal amino alcohols bearing functionalized aryl rings in high yields and enantioselectivities (up to 99% enantiomeric excess (ee)) within 0.5 h.

The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis.

BACKGROUND: Cognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases. METHODS: For this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score ≤ -1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL. RESULTS: Overall, 20.4% [40/196; 95% confidence interval (CI), 14.7-26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01-54.84; P < 0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29-46.24; P < 0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722-0.859; P < 0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%. CONCLUSIONS: In summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.

T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity.

Chimeric antigen receptor (CAR) T cell therapy lacks persistent efficacy with "on-target, off-tumor" toxicities for treating solid tumors. Thus, an antibody-guided switchable CAR vector, the chimeric Fc receptor CD64 (CFR64), composed of a CD64 extracellular domain, is designed. T cells expressing CFR64 exert more robust cytotoxicity against cancer cells than CFR T cells with high-affinity CD16 variant (CD16v) or CD32A as their extracellular domains. CFR64 T cells also exhibit better long-term cytotoxicity and resistance to T cell exhaustion compared with conventional CAR T cells. With trastuzumab, the immunological synapse (IS) established by CFR64 is more stable with lower intensity induction of downstream signaling than anti-HER2 CAR T cells. Moreover, CFR64 T cells exhibit fused mitochondria in response to stimulation, while CARH2 T cells contain predominantly punctate mitochondria. These results show that CFR64 T cells may serve as a controllable engineered T cell therapy with prolonged persistence and long-term antitumor activity.