1,4-α-Glucosidase from Fusarium solani for Controllable Biosynthesis of Silver Nanoparticles and Their Multifunctional Applications.

In the study, monodispersed silver nanoparticles (AgNPs) with an average diameter of 9.57 nm were efficiently and controllably biosynthesized by a reductase from Fusarium solani DO7 only in the presence of ß-NADPH and polyvinyl pyrrolidone (PVP). The reductase responsible for AgNP formation in F. solani DO7 was further confirmed as 1,4-α-glucosidase. Meanwhile, based on the debate on the antibacterial mechanism of AgNPs, this study elucidated in further depth that antibacterial action of AgNPs was achieved by absorbing to the cell membrane and destabilizing the membrane, leading to cell death. Moreover, AgNPs could accelerate the catalytic reaction of 4-nitroaniline, and 86.9% of 4-nitroaniline was converted to p-phenylene diamine in only 20 min by AgNPs of controllable size and morphology. Our study highlights a simple, green, and cost-effective process for biosynthesizing AgNPs with uniform sizes and excellent antibacterial activity and catalytic reduction of 4-nitroaniline.

Diffraction gratings based on a multilayer silicon nitride waveguide with high upward efficiency and large effective length.

Diffraction gratings with high upward diffraction efficiency and large effective length are required for chip-scale light detection and ranging. We propose a diffraction grating based on a multilayer silicon nitride waveguide, which theoretically achieves an upward diffraction efficiency of 92%, a near-field effective length of 376 µm, and a far-field divergence angle of 0.105° at a wavelength of 850 nm. The diffraction grating has a high tolerance to process variations based on Monte Carlo analysis. When the conditions are ±5% layer thickness variation, ±50nm lithographic variation, and ±20nm wavelength drift, more than 71% of the grating samples have a diffraction efficiency higher than 80%, and 100% of the samples have an effective length larger than 200 µm (corresponding to a far-field divergence <0.2∘). Furthermore, the near-field effective length of the grating with an upward diffraction efficiency above 90% can be adjusted from hundreds of microns to centimeters by changing the etching layer thickness and the grating duty cycle. This diffraction grating has a potential application in optical sensing and imaging from visible to near-IR wavelengths.

Interpenetration Control in Thorium Metal-Organic Frameworks: Structural Complexity toward Iodine Adsorption.

The rational design and synthesis of metal-organic frameworks with well-controlled interpenetration have been active research areas of inquiry, particularly for porosity-related applications. Herein, we extend the use of the ligand steric modulation strategy to initiate the first study of the interpenetration control of thorium-based MOFs. The approximate "hardness" of the Th4+ cation, which was conjugated with aromatic substitutions and delicately modified synthetic conditions, allows for the crystallization of single crystals of seven new Th-MOFs with five distinct topologies. Solvothermal reactions of Th(NO3)4 with the triphenyl H2TPDC ligand under variable conditions exclusively gave rise to an interpenetrated Th-MOF with a hex topology, namely Th-SINAP-16. Modifications of the ligand sterics with two pendant methyl groups to 2',5'-Me2TPDC2- and 2,2″-Me2TPDC2- afforded two noninterpenetrated UiO-68-type Th-MOFs (Th-SINAP-17 and Th-SINAP-20, respectively) with record-high pore volumes (74.8% and 75.3%, respectively) among all the thorium MOFs. Moreover, another four Th-MOFs Th-SINAP-n (n = 18, 19, 21, and 22) with three different topologies were obtained by a simple synthetic modulation. Notably, Th-SINAP-16 and Th-SINAP-21 represent the second rare examples of interpenetrated Th-MOFs reported to date. These findings revealed the unprecedented structural complexity and synthetic accessibility of Th-MOFs among all tetravalent metal containing MOFs. Such features make Th-MOFs as an ideal platform to elucidate the structure-property relationship for various applications, e.g. iodine adsorption.

Enhanced Adsorption and Separation of Xenon over Krypton via an Unsaturated Calcium Center in a Metal-Organic Framework.

Krypton (Kr) and xenon (Xe) are nowadays widely applied in technical and industrial fields. Separating and collecting highly pure Xe from nuclear facilities are necessary and urgent. However, the technology is limited due to the inert nature of Xe and other interferential factors. In this work, a calcium-based metal-organic framework, Ca-SINAP-1, which comprises a three-dimensional microporous framework with a suitable pore width, was researched for xenon and krypton separation through both experimental and theoretical methods. Ca-SINAP-1, synthesized in solvothermal and gamma ray conditions, features accessible open-metal sites, exhibits a high Xe/Kr selectivity of 10.32, and owns a Xe adsorption capacity of 2.87 mmol/g at room temperature (1.0 bar). Particularly, its excellent chemical stability (from pH 2 to 13) and thermal stability (up to 550 °C), as well as radiation-resistance (up to 400 kGy ß irradiations), render this material a promising candidate for radioactive inert gases treatment.

Differences in the clinical characteristics and outcomes of COVID-19 patients in the epicenter and peripheral areas of the pandemic from China: a retrospective, large-sample, comparative analysis.

BACKGROUND: There is limited information on the difference in epidemiology, clinical characteristics and outcomes of the initial outbreak of the coronavirus disease (COVID-19) in Wuhan (the epicenter) and Sichuan (the peripheral area) in the early phase of the COVID-19 pandemic. This study was conducted to investigate the differences in the epidemiological and clinical characteristics of patients with COVID-19 between the epicenter and peripheral areas of pandemic and thereby generate information that would be potentially helpful in formulating clinical practice recommendations to tackle the COVID-19 pandemic. METHODS: The Sichuan & Wuhan Collaboration Research Group for COVID-19 established two retrospective cohorts that separately reflect the epicenter and peripheral area during the early pandemic. The epidemiology, clinical characteristics and outcomes of patients in the two groups were compared. Multivariate regression analyses were used to estimate the adjusted odds ratios (aOR) with regard to the outcomes. RESULTS: The Wuhan (epicenter) cohort included 710 randomly selected patients, and the peripheral (Sichuan) cohort included 474 consecutive patients. A higher proportion of patients from the periphery had upper airway symptoms, whereas a lower proportion of patients in the epicenter had lower airway symptoms and comorbidities. Patients in the epicenter had a higher risk of death (aOR=7.64), intensive care unit (ICU) admission (aOR=1.66), delayed time from illness onset to hospital and ICU admission (aOR=6.29 and aOR=8.03, respectively), and prolonged duration of viral shedding (aOR=1.64). CONCLUSIONS: The worse outcomes in the epicenter could be explained by the prolonged time from illness onset to hospital and ICU admission. This could potentially have been associated with elevated systemic inflammation secondary to organ dysfunction and prolonged duration of virus shedding independent of age and comorbidities. Thus, early supportive care could achieve better clinical outcomes.

[A calcium-sensing receptor polymorphism at E942K promotes the proliferation of gastric cancer cells via Ca2+ and ERK1/2 pathways].

The study was designed to investigate the effects and mechanism of a calcium-sensing receptor (CaSR) polymorphism at E942K on the proliferation of gastric cancer cells. Single nucleotide polymorphisms (SNPs) were detected between gastric cancers group and normal controls group by DNA sequence analysis. The cell model was constructed by transfection of E942K mutant plasmid and wild-type (WT) plasmid into SGC-7901 and HEK-293 cells. The effect of E942K mutation on cell proliferation ability was detected by CCK8 and cell clone formation experiments. The effect of E942K mutation on calcium signaling was detected by calcium imaging. Western blot experiments were used to detect changes in phosphorylation levels of key proteins ERK1/2 and ß-catenin in downstream signaling pathways after E942K mutation. The results showed that the mutation rate of E942K in gastric cancer group was significantly higher than that in normal control group (P < 0.05). CCK8 and cell clone formation experiments showed that E942K mutation significantly improved the proliferation ability of SGC-7901 gastric cancer cells and HEK-293 cells. E942K mutation enhanced calcium signaling in SGC-7901 and HEK-293 cells. E942K mutation enhanced ERK1/2 phosphorylation without affecting ß-catenin phosphorylation. The results suggest that E942K mutation in CaSR may ultimately promote the proliferation of gastric cancer cells by enhancing intracellular calcium signaling and ERK1/2 phosphorylation. These results have potential clinical implications for the diagnosis and targeted therapy of gastric cancer.

Metabolic engineering of a robust Escherichia coli strain with a dual protection system.

Considerable attention has been given to the development of robust fermentation processes, but microbial contamination and phage infection remain deadly threats that need to be addressed. In this study, a robust Escherichia coli BL21(DE3) strain was successfully constructed by simultaneously introducing a nitrogen and phosphorus (N&P) system in combination with a CRISPR/Cas9 system. The N&P metabolic pathways were able to express formamidase and phosphite dehydrogenase in the host cell, thus enabled cell growth in auxotrophic 3-(N-morpholino)propanesulfonic acid medium with formamide and phosphite as nitrogen and phosphorus sources, respectively. N&P metabolic pathways also allowed efficient expression of heterologous proteins, such as green fluorescent protein (GFP) and chitinase, while contaminating bacteria or yeast species could hardly survive in this medium. The host strain was further engineered by exploiting the CRISPR/Cas9 system to enhance the resistance against phage attack. The resultant strain was able to grow in the presence of T7 phage at a concentration of up to 2 × 107 plaque-forming units/ml and produce GFP with a yield of up to 30 µg/109 colony-forming units, exhibiting significant advantages over conventional engineered E. coli. This newly engineered, robust E. coli BL21(DE3) strain therefore shows great potential for future applications in industrial fermentation.

Glucagon Like Peptide-1 (GLP-1) Modulates OVA-Induced Airway Inflammation and Mucus Secretion Involving a Protein Kinase A (PKA)-Dependent Nuclear Factor-κB (NF-κB) Signaling Pathway in Mice.

Asthma is a common chronic pulmonary inflammatory disease, featured with mucus hyper-secretion in the airway. Recent studies found that glucagon like peptide-1 (GLP-1) analogs, including liraglutide and exenatide, possessed a potent anti-inflammatory property through a protein kinase A (PKA)-dependent signaling pathway. Therefore, the aim of current study was to investigate the value of GLP-1 analog therapy liraglutide in airway inflammation and mucus secretion in a murine model of ovalbumin (OVA)-induced asthma, and its underlying molecular mechanism. In our study, BALB/c mice were sensitized and challenged by OVA to induce chronic asthma. Pathological alterations, the number of cells and the content of inflammatory mediators in bronchoalveolar lavage fluid (BALF), and mucus secretion were observed and measured. In addition, the mRNA and protein expression of E-selectin and MUC5AC were analyzed by qPCR and Western blotting. Then, the phosphorylation of PKA and nuclear factor-κB (NF-κB) p65 were also measured by Western blotting. Further, NF-κB p65 DNA binding activity was detected by ELISA. OVA-induced airway inflammation, airway mucus hyper-secretion, the up-regulation of E-selectin and MUC5AC were remarkably inhibited by GLP-1 in mice (all p < 0.01). Then, we also found that OVA-reduced phosphorylation of PKA, and OVA-enhanced NF-κB p65 activation and NF-κB p65 DNA binding activity were markedly improved by GLP-1 (all p < 0.01). Furthermore, our data also figured out that these effects of GLP-1 were largely abrogated by the PKA inhibitor H-89 (all p < 0.01). Taken together, our results suggest that OVA-induced asthma were potently ameliorated by GLP-1 possibly through a PKA-dependent inactivation of NF-κB in mice, indicating that GLP-1 analogs may be considered an effective and safe drug for the potential treatment of asthma in the future.

Time-dependent expression of PEDF and VEGF in blood serum and retina of rats with oxygen-induced retinopathy.

The effects of the balance changes of pigment epithelium growth factor (PEDF) and vascular endothelial growth factor (VEGF) in whole-body and retinal tissue on rats with oxygen-induced retinopathy were investigated. Forty-eight neonatal SD rats at the age of 7 days were randomly divided into 4 groups. The neonatal rats in experimental groups were exposed to 75% to 80% oxygen for 5 days and then to normal air, and those in control groups were kept feeding in normal air. At the age of 17 and 22 days, all the neonatal rats received retina angiography with FITC-dextran and the pathological changes of retinal vessels and perfusion were observed. HE staining of the tissue section and the number counting of endothelial cells extending beyond the inner limiting membrane were performed to evaluate the endothelial proliferation. Immunohistochemistry was applied to detect the expression of PEDF and VEGF in retinal tissue, and ELISA to detect their expression in serum. A hypoxic-ischemic proliferation of retina and more endothelial cells extending beyond the inner limiting membrane were found in the neonatal rats in both experimental groups of 17-day old and 22-day old as compared with those in control group with the difference being statistically significant (P<0.01). VEGF staining of the rats in the 17-day old experimental group was significantly stronger, with an increasing positive rate, than that of the rats in the 17-day old control group (P<0.01). PEDF staining of the rats of 22 days old was weaker than that of the rats of 17 days old in the experimental groups (P<0.01). There was no significant difference in serum VEGF concentration among all groups (P>0.05). The serum PEDF concentration in the rats of 17 days old in experimental group was decreased significantly as compared with that in the rats of 17 days old in control group (P<0.01), and in experimental groups, the serum PEDF concentration of the rats of 22 days old was increased as compared with that of the rats of 17 days old (P<0.01). In conclusion, the obviously decreased serum PEDF concentration and the abnormal enhanced expression of VEGF density in local retinal tissue broke down the balance of PEDF/VEGF in whole-body or local tissues, which might play an important role in retinal vascular proliferation.

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

Undifferentiated embryonic cell transcription factor-1 (UTF1) inhibits the growth of cervical cancer cells by transactivating p27Kip1.

Undifferentiated embryonic cell transcription factor-1 (UTF1) is an important transcription factor during development, which plays critical roles in cell fate determination. However, its expression and function in somatic tissues remain unclear. Here, we investigated the expression pattern of the UTF1 in the human normal and cancerous lesions of cervix and found that UTF1 was downregulated in cervical carcinogenesis, which was related to the hypermethylation of UTF1 promoter. Exogenous expression of UTF1 resulted in the significant inhibition of cell proliferation in vitro and tumorigenesis in vivo through attenuating cell cycle arrest via increasing the level of p27 (Kip1) . Luciferase reporter assay indicated that the region containing an intact activating transcription factor site between nucleotides -517 and -388 of the p27 (Kip1) promoter was indispensable for its activation by UTF1. Chromatin immunoprecipitation analysis confirmed the physical interaction between UTF1 and the p27 (Kip1) promoter. Taken together, our findings reveal that UTF1 attenuates cell proliferation and is inactivated in cervical carcinogenesis through epigenetic modification, which strongly supports that UTF1 is a potential tumor suppressor.

Quantification of serum hepatitis B surface antigen in predicting the response of pegylated interferon alfa-2a in HBeAg-positive chronic hepatitis B with prior lamivudine exposure.

AIMS: Majority of previous studies of pegylated interferon α-2a (PegIFNα-2a) forced on naïve chronic hepatitis B (CHB) patients, and the data of PegIFNα-2a in therapy of patients with prior exposure to nucleos(t)ide analogues is rare. This study aimed to investigate the predictive role of serum quantitative hepatitis B surface antigen (HBsAg) in predicting sustained response of PegIFNα-2a in HBeAg-positive CHB patients with prior lamivudine exposure. METHODS: Forty-six patients with prior lamivudine exposure received PegIFNα-2a for 12 months and followed-up for 6 months. The clinical features of responders and non-responders were compared, and the predictive role of quantitative HBsAg in predicting responders at the end of follow-up was evaluated. Responders were defined as an ALT normalization, HBeAg seroconversion and sustained virological response at the end of follow-up. RESULTS: In this cohort, only 26.1% (12/46) patients were responders. The baseline characteristics of the responders and non-responders were similar; however, the rates of ALT normalization, HBV DNA undetectability and HBeAg seroconversion were all significantly higher in responders than that in non-responders. During the treatment and follow-up, the HBsAg levels were all significantly lower in responders than that in non-responders. In predicting reponders, the serum HBsAg cutoff of 6000 IU/mL at months 6 had a positive predictive value of 73.3 and a negative predictive value of 96.8%, and with an area under the receiver operating characteristic curve of 0.869. CONCLUSION: The responders toward PegIFNα-2a in CHB patients with prior lamivudine exposure is not high, and serum HBsAg <6000 IU/Ml at months 6 of on-treatment had a high value to predict long-term outcomes of treatment.

Probucol ameliorates the development of nonalcoholic steatohepatitis in rats fed high-fat diets.

AIMS: We sought to evaluate the effects of probucol on steatohepatitis and associated molecular mechanisms in a rat model of nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). METHODS: Forty male rats weighing 100-120 g were randomly assigned to the following treatments (n = 10 for each treatment): standard diet + normal saline (NC group), standard diet + 500 mg/kg/day probucol (NP group), HFD + normal saline (HD group), and HFD + 500 mg/kg/day probucol (HP group). All animals received the above treatments for 15 weeks. Lipid metabolism and steatohepatitis were assessed. Systemic insulin resistance, oxidative stress status, serum tumor necrosis factor-alpha (TNF-α) and adiponectin levels, and gene expression were examined. RESULTS: High-fat feeding resulted in macrovesicular steatosis, lobular inflammation, and hepatocellular ballooning degeneration in the liver, coupled with increased concentrations of serum aspartate aminotransferase and alanine aminotransferase. Probucol exposure attenuated the biochemical and histological changes comparable with NASH. Moreover, probucol treatment significantly prevented the elevations of serum total cholesterol, low-density lipoprotein, and high-density lipoprotein and the increase in the expression of numerous lipid metabolism-related genes in HFD-fed rats. There were increased insulin sensitivity and serum adiponectin levels and enhanced hepatic AMP-activated protein kinase phosphorylation in the HP group. Probucol lessened the HFD-induced elevation of serum TNF-α and hepatic malondialdehyde and reduced antioxidant enzymatic activities. CONCLUSIONS: Probucol shows beneficial effects on HFD-induced steatohepatitis by improving insulin resistance and attenuating oxidative stress and systemic inflammation.

Polyneuropathy organomegaly endocrinopathy M-protein and skin changes syndrome with ascites as an early-stage manifestation: A case report.

BACKGROUND: Polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome caused by a potential plasma cell tumor. The clinical manifestations of POEMS syndrome are diverse. Due to the insidious onset and lack of specific early-stage manifestations, POEMS syndrome is easily misdiagnosed or never diagnosed, leading to delayed treatment. Neurological symptoms are usually the first clinical manifestation, while ascites is a rare symptom in patients with POEMS syndrome. CASE SUMMARY: A female patient presented with unexplained ascites as an initial symptom, which is a rare early-stage manifestation of the condition. After 1 year, the patient gradually developed progressive renal impairment, anemia, polyserosal effusion, edema, swollen lymph nodes on the neck, armpits, and groin, and decreased muscle strength of the lower extremities. The patient was eventually diagnosed with POEMS syndrome after multidisciplinary team discussion. Treatment comprised bortezomib + dexamethasone, continuous renal replacement therapy, chest and abdominal closed drainage, transfusions of erythrocytes and platelets, and other symptomatic and supportive treatments. The patient's condition initially improved after treatment. However, then her symptoms worsened, and she succumbed to the illness and died. CONCLUSION: Ascites is a potential early manifestation of POEMS syndrome, and this diagnosis should be considered for patients with unexplained ascites. Furthermore, multidisciplinary team discussion is helpful in diagnosing POEMS syndrome.

Construction of cyclopenta[b]dihydronaphthofurans via TsOH-catalyzed consecutive biscyclization of dithioallylic alcohols and 1-styrylnaphthols.

An efficient TsOH-catalyzed consecutive biscyclization cascade reaction of dithioallylic alcohols with 1-styrylnaphthols is demonstrated for the concise construction of pharmaceutically important cyclopenta[b]dihydrobenzofuran scaffolds. This process involved an acid-catalyzed (3+2) cycloaddition followed by an intramolecular nucleophilic addition, providing cyclopenta[b]dihydronaphthofurans bearing a tetra- or fully substituted cyclopentane core in good yields with exclusive diastereoselectivities (>20 : 1 d.r.).

Myofascial acupuncture versus routine acupuncture for mechanical neck pain: a protocol for a multicentre randomised controlled trial.

INTRODUCTION: Mechanical neck pain (MNP) is defined as pain in the area of the neck and/or neck-shoulder provoked by body mechanics and which adversely affects physical, psychological and social function. The treatments for MNP are limited. Previous studies and clinical experience have indicated that myofascial acupuncture might be a better treatment option for MNP, but the efficacy is controversial. Therefore, our aim is to compare the efficacy of myofascial acupuncture and routine acupuncture for MNP. METHODS AND ANALYSIS: The study is a multicentre, prospective randomised clinical trial. Patients will be recruited from four tertiary hospitals in China. A total of 438 participants with MNP will be randomly assigned into two groups, namely the 'Sancai-Tianbu' myofascial acupuncture group and the routine acupuncture group, at a ratio of 1:1. Each group will receive the acupuncture treatment twice a week for 21 days, totalling six sessions. The primary outcome will be the Visual Analogue Scale score. The secondary outcomes will be the Neck Disability Index, the cervical range of motion and the MOS 36-Item Short Form Health Survey. The assessments will be performed at baseline (immediately after allocation), pretreatment (5 min before every treatment), post-treatment (within 10 min after every treatment), postcourse (within 1 day after the course), and at 1, 3 and 6 months after the course. All patients will be included in the intent-to-treat analysis. Repeated-measure analysis of covariance will be used to determine the effects of the intervention on the outcome measures. ETHICS AND DISSEMINATION: Ethics approval was obtained from China Aerospace Science & Industry Corporation 731 Hospital, with permission number 2022-0204-01. Written informed consent will be obtained from the enrolled patients. Trial results will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2200061453.

CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor.

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.

Development of a deep pathomics score for predicting hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND AND PURPOSE: Tumor recurrence after liver transplantation (LT) impedes the curative chance for hepatocellular carcinoma (HCC) patients. This study aimed to develop a deep pathomics score (DPS) for predicting tumor recurrence after liver transplantation using deep learning. PATIENTS AND METHODS: Two datasets of 380 HCC patients who underwent LT were enrolled. Residual convolutional neural networks were used to identify six histological structures of HCC. The individual risk score of each structure and DPS were derived by a modified DeepSurv network. Cox regression analysis and Concordance index were used to evaluate the prognostic significance. The cellular exploration of prognostic immune biomarkers was performed by quantitative and spatial proximity analysis according to three panels of 7-color immunofluorescence. RESULTS: The overall classification accuracy of HCC tissue was 97%. At the structural level, immune cells were the most significant tissue category for predicting post-LT recurrence (HR 1.907, 95% CI 1.490-2.440). The C-indices of DPS achieved 0.827 and 0.794 in the training and validation cohorts, respectively. Multivariate analysis for recurrence-free survival (RFS) showed that DPS (HR 4.795, 95% CI 3.017-7.619) was an independent risk factor. Patients in the high-risk subgroup had a shorter RFS, larger tumor diameter and a lower proportion of clear tumor borders. At the cellular level, a higher infiltration of intratumoral NK cells was negatively correlated with recurrence risk. CONCLUSIONS: This study established an effective DPS. Immune cells were the most significant histological structure related to HCC recurrence. DPS performed well in post-LT recurrence prediction and the identification of clinicopathological features.