Gut cytokines modulate olfaction through metabolic reprogramming of glia.

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival1,2. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms3-5. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviours remains unknown. Here we show that enteropathogen infection in Drosophila can modulate olfaction through metabolic reprogramming of ensheathing glia of the antennal lobe. Infection-induced unpaired cytokine expression in the intestine activates JAK-STAT signalling in ensheathing glia, inducing the expression of glial monocarboxylate transporters and the apolipoprotein glial lazarillo (GLaz), and affecting metabolic coupling of glia and neurons at the antennal lobe. This modulates olfactory discrimination, promotes the avoidance of bacteria-laced food and increases fly survival. Although transient in young flies, gut-induced metabolic reprogramming of ensheathing glia becomes constitutive in old flies owing to age-related intestinal inflammation, which contributes to an age-related decline in olfactory discrimination. Our findings identify adaptive glial metabolic reprogramming by gut-derived cytokines as a mechanism that causes lasting changes in a sensory system in ageing flies.

Spermatogenic cell-specific type 1 hexokinase (HK1S) is essential for capacitation-associated increase in tyrosine phosphorylation and male fertility in mice.

Hexokinase (HK) catalyzes the first irreversible rate-limiting step in glycolysis that converts glucose to glucose-6-phosphate. HK1 is ubiquitously expressed in the brain, erythrocytes, and other tissues where glycolysis serves as the major source of ATP production. Spermatogenic cell-specific type 1 hexokinase (HK1S) is expressed in sperm but its physiological role in male mice is still unknown. In this study, we generate Hk1s knockout mice using the CRISPR/Cas9 system to study the gene function in vivo. Hk1s mRNA is exclusively expressed in testes starting from postnatal day 18 and continuing to adulthood. HK1S protein is specifically localized in the outer surface of the sperm fibrous sheath (FS). Depletion of Hk1s leads to infertility in male mice and reduces sperm glycolytic pathway activity, yet they have normal motile parameters and ATP levels. In addition, by using in vitro fertilization (IVF), Hk1s deficient sperms are unable to fertilize cumulus-intact or cumulus-free oocytes, but can normally fertilize zona pellucida-free oocytes. Moreover, Hk1s deficiency impairs sperm migration into the oviduct, reduces acrosome reaction, and prevents capacitation-associated increases in tyrosine phosphorylation, which are probable causes of infertility. Taken together, our results reveal that HK1S plays a critical role in sperm function and male fertility in mice.

Installing a Trigger to Upcycle High-Density Polyethylene.

Creating C═C bonds as "weak" sites in the stable C-C chains of polyethylene (PE) is an appealing strategy to promote sustainable development of the polyolefin industry. Compared to methods, such as dehydrogenation and postpolymerization modification, the copolymerization of ethylene (E) and butadiene (BD) should be a convenient and direct approach to introduce C═C bonds in PE, whereas it encounters problems in controlling the composition and regularity of the copolymer due to the mismatched activities and mechanisms between the two monomers. Herein, we report by employing the amidinate gadolinium complex, controllable E/BD copolymerization was achieved, where BD was incorporated in the uniformly discrete 1,4 mode. The obtained copolymer possesses the same physical, mechanical, processing, and antioxygen (aging at 100 °C for 28 days) properties as commercial high-density-PE, which, strikingly, were degraded by C═C bonds into α,ω-telechelic oligomers with narrow distribution. These degraded functional products were transferred to compatibilizers via atom-transfer radical polymerization or immortal ring-opening polymerization, achieving upcycling.

NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.

BACKGROUND: Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required. METHODS: We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo. RESULTS: HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation. CONCLUSION: We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential.

The Effect of Reactive Oxygen Species on Respiratory Complex I Activity in Liposomes.

Respiratory complex I (R-CI) is an essential enzyme in the mitochondrial electron transport chain but also a major source of reactive oxygen species (ROS), which are implicated in neurodegenerative diseases and ageing. While the mechanism of ROS production by R-CI is well-established, the feedback of ROS on R-CI activity is poorly understood. Here, we perform EPR spectroscopy on R-CI incorporated in artificial membrane vesicles to reveal that ROS (particularly hydroxyl radicals) reduce R-CI activity by making the membrane more polar and by increasing its hydrogen bonding capability. Moreover, the mechanism that we have uncovered reveals that the feedback of ROS on R-CI activity via the membrane is transient and not permanent; lipid peroxidation is negligible for the levels of ROS generated under these conditions. Our successful use of modular proteoliposome systems in conjunction with EPR spectroscopy and other biophysical techniques is a powerful approach for investigating ROS effects on other membrane proteins.

Impact of preoperative antiviral therapy on the prognosis of hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. METHODS: 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People's Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. RESULTS: NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA < 1000 copy/mL had significantly better recurrence-free survival (RFS) and OS than those with HBV DNA ≥ 1000 copy/mL (HR: 7.783; P = 0.002; HR: 6.699; P < 0.001). However, the differences of RFS and OS rates between entecavir group and tenofovir disoproxil fumarate group were not statistically significant. Similar results were also observed in the rates of early VR, BR and combined VR and BR. CONCLUSION: Timely and reasonable preoperative NAs therapy showed clinical benefit in improving the prognosis of patients with HBV-related HCC, even in the case of normal alanine aminotransferase (ALT) level and negative hepatitis e antigen (HBeAg). Furthermore, a possible synergistic effect between antiviral therapy and anti-PD-1 therapy was founded and need further verification.

Metabolism of asparagine in the physiological state and cancer.

Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Activation-Induced Cytidine Deaminase Impacts the Primary Antibody Repertoire in Naive Mice.

Genetic and environmental cues shape the evolution of the B cell Ig repertoire. Activation-induced cytidine deaminase (AID) is essential to generating Ig diversity through isotype class switching and somatic mutations, which then directly influence clonal selection. Impaired B cell development in AID-knockout mice has made it difficult to study Ig diversification in an aging repertoire. Therefore, in this report, we used a novel inducible AID-knockout mouse model and discovered that deleting AID in adult mice caused spontaneous germinal center formation. Deep sequencing of the IgH repertoire revealed that Ab diversification begins early in life and evolves over time. Our data suggest that activated B cells form germinal centers at steady state and facilitate continuous diversification of the B cell repertoire. In support, we identified shared B cell lineages that were class switched and showed age-dependent rates of mutation. Our data provide novel context to the genesis of the B cell repertoire that may benefit the understanding of autoimmunity and the strength of an immune response to infection.

Single-molecule nanopore sequencing reveals extreme target copy number heterogeneity in arylomycin-resistant mutants.

Tandem gene amplification is a frequent and dynamic source of antibiotic resistance in bacteria. Ongoing expansions and contractions of repeat arrays during population growth are expected to manifest as cell-to-cell differences in copy number (CN). As a result, a clonal bacterial culture could comprise subpopulations of cells with different levels of antibiotic sensitivity that result from variable gene dosage. Despite the high potential for misclassification of heterogenous cell populations as either antibiotic-susceptible or fully resistant in clinical settings, and the concomitant risk of inappropriate treatment, CN distribution among cells has defied analysis. Here, we use the MinION single-molecule nanopore sequencer to uncover CN heterogeneity in clonal populations of Escherichia coli and Acinetobacter baumannii grown from single cells isolated while selecting for resistance to an optimized arylomycin, a member of a recently discovered class of Gram-negative antibiotic. We found that gene amplification of the arylomycin target, bacterial type I signal peptidase LepB, is a mechanism of unstable arylomycin resistance and demonstrate in E. coli that amplification instability is independent of RecA. This instability drives the emergence of a nonuniform distribution of lepB CN among cells with a range of 1 to at least 50 copies of lepB identified in a single clonal population. In sum, this remarkable heterogeneity, and the evolutionary plasticity it fuels, illustrates how gene amplification can enable bacterial populations to respond rapidly to novel antibiotics. This study establishes a rationale for further nanopore-sequencing studies of heterogeneous cell populations to uncover CN variability at single-molecule resolution.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials. METHODS: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering. RESULTS: We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering. DISCUSSION: CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain. HIGHLIGHTS: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09. CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism. Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.

Supernatural Beliefs-Based Intervention to Improve Type-2 Diabetes Self-Management: A Pilot Randomized Controlled Trial from China.

China has over 100 million people living with type 2 diabetes mellitus (T2DM). Interventions framed around pre-existing personal beliefs in the supernatural may improve T2DM self-management, but such interventions are lacking in China. This pilot randomized controlled trial (RCT) assessed the feasibility of a full-scale RCT to evaluate the efficacy of a supernatural beliefs-based intervention on T2DM management self-efficacy in China. In 2019, 62 T2DM patients were enrolled at two hospitals in Suzhou, China. Participants were randomly assigned to view a 30-s control or intervention video at baseline. The control video showed general diabetes self-management information. The intervention video showed identical information, but also indicated that some diabetics with supernatural beliefs (chao ziran xinnian) have lower glycemic levels, because their beliefs enhance their confidence in diabetes self-management. Development of the intervention was guided by the theory of planned behavior and literature on spiritual framing health interventions. Baseline and follow-up measures after two weeks were assessed by interviewer administered surveys in-person and by telephone, respectively. Diabetes management self-efficacy was assessed with the diabetes management self-efficacy scale. Randomization of intervention allocation appeared to be successful. However, follow-up retention was low, especially for the intervention group (3% vs. 31%). A full-size efficacy RCT using the current study design is unlikely to succeed. T2DM patients shown the supernatural beliefs-based intervention had significantly higher loss to follow-up that was insurmountable. T2DM patients in Suzhou, China may not be receptive to brief, non-tailored supernatural beliefs-based interventions delivered to a general population in clinical settings.

Mitochondrial Protease Targeting Chimeras for Mitochondrial Matrix Protein Degradation.

Targeted protein degradation (TPD) is an emerging technique for protein regulation. Currently, all TPD developed in eukaryotic cells relies on either ubiquitin-proteasome or lysosomal systems, thus are powerless against target proteins in membrane organelles lacking proteasomes and lysosomes, such as mitochondria. Here, we developed a mitochondrial protease targeting chimera (MtPTAC) to address this issue. MtPTAC is a bifunctional small molecule that can bind to mitochondrial caseinolytic protease P (ClpP) at one end and target protein at the other. Mechanistically, MtPTAC activates the hydrolase activity of ClpP while simultaneously bringing target proteins into proximity with ClpP. Taking mitochondrial RNA polymerase (POLRMT) as a model protein, we have demonstrated the powerful proteolytic ability and antitumor application prospects of MtPTAC, both in vivo and in vitro. This is the first modularly designed TPD that can specifically hydrolyze target proteins inside mitochondria.

Broadband, compact and reflection-less silicon polarizer and polarization beam splitter using chirped anti-symmetric multimode nanobeams.

We present chirped anti-symmetric multimode nanobeams (CAMNs) based on silicon-on-insulator platforms, and describe their applications as broadband, compact, reflection-less, and fabrication-tolerant TM-pass polarizers and polarization beam splitters (PBSs). The anti-symmetric structural perturbations of a CAMN ensure that only contradirectional coupling between symmetric and anti-symmetric modes is possible, which can be exploited to block the unwanted back reflection of the device. The new possibility of introducing a large chirp on an ultra-short nanobeam-based device to overcome the operation bandwidth limitation due to the coupling coefficient saturation effect is also shown. The simulation results show that an ultra-compact CAMN with a length of ∼4.68 um can be used to develop a TM-pass polarizer or a PBS with an ultra-broad 20 dB extinction ratio (ER) bandwidth of >300 nm and an average insertion loss of <1.3 dB. The CAMN-based polarizer and PBS were fabricated and experimentally characterized in a wavelength range from 1507 to 1575 nm. The measured ERs were >20 dB over the entire tested wavelength range and the average insertion losses were <0.5 dB for both devices. The mean reflection suppression ratio of the polarizer was ∼26.4 dB. Large fabrication tolerances of ±60 nm in the waveguide widths of the devices were also demonstrated.

Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism.

Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by liver injury. Currently, there are no approved therapies for liver fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed a prominent therapeutic effect on liver diseases. However, few studies have evaluated therapeutic effect of hADMSCs-Exo in liver fibrosis and cirrhosis, and its precise mechanisms of action remain unclear. Herein, we investigated anti-fibrotic efficacy of hADMSCs-Exo in vitro and in vivo, and identified important metabolic changes and the detailed mechanism through transcriptomic and metabolomic profiling. We found hADMSCs-Exo could inhibit the proliferation of activated hepatic stellate cells through aggravating apoptosis and arresting G1 phase, effectively inhibiting the expression of profibrogenic proteins and epithelial-to-mesenchymal transition (EMT) in vitro. Moreover, it could significantly block collagen deposition and EMT process, improve liver function and reduce liver inflammation in liver cirrhosis mice model. The omics analysis revealed that the key mechanism of hADMSCs-Exo anti-hepatic fibrosis was the inhibition of PI3K/AKT/mTOR signaling pathway and affecting the changes of metabolites in lipid metabolism, and mainly regulating choline metabolism. CHPT1 activated by hADMSCs-Exo facilitated formation and maintenance of vesicular membranes. Thus, our study indicates that hADMSCs-Exo can attenuate hepatic stellate cell activation and suppress the progression of liver fibrosis, which holds the significant potential of hADMSCs-Exo for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases.

Single-Molecule Imaging Reveals Differential AT1R Stoichiometry Change in Biased Signaling.

G protein-coupled receptors (GPCRs) represent promising therapeutic targets due to their involvement in numerous physiological processes mediated by downstream G protein- and ß-arrestin-mediated signal transduction cascades. Although the precise control of GPCR signaling pathways is therapeutically valuable, the molecular details for governing biased GPCR signaling remain elusive. The Angiotensin II type 1 receptor (AT1R), a prototypical class A GPCR with profound implications for cardiovascular functions, has become a focal point for biased ligand-based clinical interventions. Herein, we used single-molecule live-cell imaging techniques to evaluate the changes in stoichiometry and dynamics of AT1R with distinct biased ligand stimulations in real time. It was revealed that AT1R existed predominantly in monomers and dimers and underwent oligomerization upon ligand stimulation. Notably, ß-arrestin-biased ligands induced the formation of higher-order aggregates, resulting in a slower diffusion profile for AT1R compared to G protein-biased ligands. Furthermore, we demonstrated that the augmented aggregation of AT1R, triggered by activation from each biased ligand, was completely abrogated in ß-arrestin knockout cells. These findings furnish novel insights into the intricate relationship between GPCR aggregation states and biased signaling, underscoring the pivotal role of molecular behaviors in guiding the development of selective therapeutic agents.

Bipolar Membrane Electrodialysis for Direct Conversion of L-Ornithine Monohydrochloride to L-Ornithine.

In this study, bipolar membrane electrodialysis was proposed to directly convert L-ornithine monohydrochloride to L-ornithine. The stack configuration was optimized in the BP-A (BP, bipolar membrane; A, anion exchange membrane) configuration with the Cl- ion migration through the anion exchange membrane rather than the BP-A-C (C, cation exchange membrane) and the BP-C configurations with the L-ornithine+ ion migration through the cation exchange membrane. Both the conversion ratio and current efficiency follow BP-A > BP-A-C > BP-C, and the energy consumption follows BP-A < BP-A-C < BP-C. Additionally, the voltage drop across the membrane stack (two repeating units) and the feed concentration were optimized as 7.5 V and 0.50 mol/L, respectively, due to the low value of the sum of H+ ions leakage (from the acid compartment to the base compartment) and OH- ions migration (from the base compartment to the acid compartment) through the anion exchange membrane. As a result, high conversion ratio (96.1%), high current efficiency (95.5%) and low energy consumption (0.31 kWh/kg L-ornithine) can be achieved. Therefore, bipolar membrane electrodialysis is an efficient, low energy consumption and environmentally friendly method to directly convert L-ornithine monohydrochloride to L-ornithine.

Surface-Engineered Gold Nanoclusters for Stimulated Emission Depletion and Correlated Light and Electron Microscopy Imaging.

Stimulated emission depletion (STED) nanoscopy is an emerging super-resolution imaging platform for the study of the cellular structure. Developing suitable fluorescent probes of small size, good photostability, and easy functionalization is still in demand. Herein, we introduce a new type of surface-engineered gold nanoclusters (Au NCs) that are ultrasmall (1.7 nm) and ultrabright (QY = 60%) for STED bioimaging. A rigid shell formed by l-arginine (l-Arg) and 6-aza-2-thiothymine (ATT) on the Au NC surface enables not only its strong fluorescence in aqueous solution but also its easy chemical modification for specific biomolecule labeling. Au NCs show remarkable performance as STED nanoprobes, including high depletion efficiency, good photobleaching resistance, and low saturation intensity. Super-resolution imaging has been achieved with these Au NCs, and targeted nanoscopic imaging of cellular tubulin has been demonstrated. Moreover, the circular structure of lysosomes in live cells has been revealed. As a Au NC is also an ideal probe for electron microscopy, dual imaging of Aß42 aggregates with the single labeling probe of Au NCs has been realized in correlative light and electron microscopy (CLEM). This work reports, for the first time, the application of Au NCs as a novel probe in STED and CLEM imaging. With their excellent properties, Au NCs show promising potential for nanoscale bioimaging.

Ultra-low loss SiN edge coupler interfacing with a single-mode fiber.

In this work, an ultra-low loss silicon nitride (SiN) edge coupler was designed and fabricated to interface with a single-mode fiber (SMF). Unlike other works that focus on the core structure, this work focuses on the cladding structure. First, it is demonstrated that the cladding structure ultimately determines the size and shape of the mode when the taper tip width is small enough. Then, the thickness of the up-cladding is optimized to provide enough space for mode expansion in the vertical direction. Air trenches are added to confine the mode laterally. In addition, the refractive index (RI) of the up-cladding layer is slightly increased to prevent light from leaking into the Si substrate. This edge coupler is then fabricated on the SiN platform at Chongqing United Microelectronics Center. For the TE mode at 1630 nm, a coupling loss of 0.67 dB/facet was obtained. At 1550 nm, 0.85 dB/facet and 1.09 dB/facet were measured for the TE and TM modes, respectively, which means that the polarization-dependent loss is 0.24 dB. Although the design method and the structure are based on a pure SiN platform, they are applicable to a silicon-on-insulator platform as well.

Comparative study of indocyanine green (ICG)-R15 and Albumin-Indocyanine Green Evaluation (ALICE) grading system in the prediction of posthepatectomy liver failure and postoperative mortality in patients with hepatic alveolar echinococcosis.

BACKGROUND: A precise evaluation of liver reserve function in patients with hepatic alveolar echinococcosis (HAE) prior to hepatectomy could substantially increase the success rate of the operation and reduce the incidence of postoperative complications. The present study aimed to investigate the significance of the indocyanine green retention test at 15 min (ICG-R15) and the Albumin-Indocyanine Green Evaluation (ALICE) grading system in predicting severe posthepatectomy liver failure (PHLF) and postoperative mortality in HAE patients undergoing liver resection. METHODS: A total of 105 HAE patients undergoing hepatectomy were enrolled in this study. The value of each variable in predicting severe PHLF was evaluated by univariate and multivariate logistic regression analyses. The area under the receiver operating characteristic (ROC) curves (AUC) were calculated to evaluate the predictive ability of the Child-Pugh grade, ICG-R15, and ALICE grading system. Also, patients were classified using the optimal cutoff value for ICG-R15 and different ALICE grades, and the incidence of severe PHLF and postoperative mortality were compared with the predicted values. RESULTS: Out of the 105 HAE patients enrolled in this study, 34 patients (32.4%) developed severe PHLF. The ALICE grade and operative time were identified as independent predictors of severe PHLF. According to ROC analysis, the AUCs of the Child-Pugh grade, ICG-R15, and ALICE grade for predicting severe PHLF were 0.733 (95% confidence interval (CI), 0.637-0.814), 0.823 (95% CI, 0.737-0.891), 0.834 (95% CI, 0.749-0.900). The incidence of severe PHLF and postoperative 90-day mortality in patients with ICG-R15 > 7.2% were significantly higher than those with ICG-R15 ≤ 7.2% (P < 0.001; P = 0.008). Likewise, the incidence of severe PHLF and postoperative 90-day mortality in patients with ALICE grade 2 were higher than those with ALICE grade 1 within the Child-Pugh grade A (P < 0.001; P = 0.083). CONCLUSION: ICG-R15 and ALICE grading system are powerful predictors of severe PHLF and postoperative mortality among HAE patients undergoing hepatectomy. Furthermore, a combination of the preoperative Child-Pugh grade and ALICE grading system may provide an even more precise and objective guidance and facilitate surgical decision-making for HAE patients.

Prognostic value of inflammation-immunity-nutrition score in patients with hepatocellular carcinoma treated with anti-PD-1 therapy.

BACKGROUND: There are no validated biomarkers that can predict the clinical benefit of immune checkpoint blockers against the programmed cell death protein 1 (PD-1) treatments in hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of inflammation-immunity-nutrition score (IINS) in patients with HCC treated with anti-PD-1 therapy. METHODS: A consecutive series of 101 HCC patients treated with PD-1 inhibitors in Sichuan Provincial People's Hospital between January 2018 and August 2020 were enrolled in the retrospective study. IINS (0-6) was constructed based on pretreatment high-sensitivity C-reactive protein (hsCRP), lymphocyte (LYM), and albumin (ALB). The patients were divided into high and low IINS groups according to IINS values. Prognostic values of each variable were evaluated with univariate and multivariate time-dependent Cox regression analyses. Survival curves were calculated and compared using the Kaplan-Meier method and log-rank test. The prognostic performance of IINS was further compared with that of other traditional prognostic indicators by receiver operating characteristic (ROC) curve and the areas under the ROC curve. RESULTS: Patients with low IINS had longer overall survival (OS) (HR: 4.711, 95% CI: 1.80-12.37, p = .001) and progression-free survival (HR: 3.411, 95% CI: 1.79-6.51, p < .0001) than those with high IINS. The multivariate analysis identified IINS (HR: 3.746, 95% CI: 1.05-13.38, p = .042) and tumor number (HR: 5.111, 95% CI: 1.075-24.299, p = .04) as independent prognostic factors. According to ROC analysis, IINS (AUC =0.729, 95% CI: 0.597-0.861, p = .002) presented better prognostic performance than other traditional prognostic indicators. The area of the IINS-CA19-9 under the ROC curve (AUC) was higher than that of the IINS or CA19-9 levels for the prediction of OS. CONCLUSION: The results suggest that IINS may be an independent prognostic indicator for HCC patients treated with anti-PD-1 therapy. IINS-CA19-9 classification may be more effective in predicting clinical benefit of anti-PD-1 therapy in HCC patients.