Mining the interpretable prognostic features from pathological image of intrahepatic cholangiocarcinoma using multi-modal deep learning.

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.

Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

[Effect of Pterostilbene Regulating Nuclear Factor E2-Related Factor 2 on Apoptosis of Colon Cancer Cells in Vitro].

Objective To investigate the effects of pterostilbene on human colon cancer LoVo cells and study the regulatory mechanism of nuclear factor E2-related factor 2 (Nrf2) in the process of pterostilbene acting on LoVo cells. Methods LoVo cells were treated with different concentrations (5,10,20,40,60,80,100 µmol/L) of pterostilbene.Cell viability,migration,invasion,and apoptosis were examined by CCK-8,scratch,Transwell,and TUNEL assays,respectively.The mitochondrial membrane potential was measured by the mitochondrial membrane potential assay kit with JC-1.The reactive oxygen species level was measured by 2',7'-dichlorofluorescein diacetate.The protein levels of Nrf2,phosphorylated Nrf2,heme oxygenase 1,and apoptotic proteins (Bcl2 and Bax) were determined by Western blotting.In addition,cell viability,Nrf2 expression,and apoptosis rate were determined after co-application of the Nrf2-specific agonist sulforaphane. Results Compared with the control group,40,60,80,100 µmol/L pterostilbene reduced the viability of LoVo cells (P=0.014,P<0.001,P<0.001,P<0.001).Pterostilbene at 5,10,20 µmol/L did not show effects on cell viability but inhibited cell migration (P=0.008,P<0.001,P<0.001) and invasion (all P<0.001).Pterostilbene at 40,60,80 µmol/L increased apoptosis (P=0.014,P<0.001,P<0.001),promoted mitochondrial membrane potential depolarization (P=0.026,P<0.001,P<0.001) and reactive oxygen species accumulation (all P<0.001),and down-regulated the expression of phosphorylated Nrf2 (P=0.030,P<0.001,P<0.001),heme oxygenase 1 (P=0.015,P<0.001,P<0.001),and Bcl2 (P=0.039,P<0.001,P<0.001) in LoVo cells.Pterostilbene at 60,80 µmol/L down-regulated Nrf2 expression (P=0.001,P<0.001) and up-regulated Bax expression (both P<0.001).The application of sulforaphane reversed the effects of pterostilbene on cell viability (P<0.001),apoptosis (P<0.001),and Nrf2 expression (P=0.022). Conclusion Pterostilbene is a compound that can effectively inhibit colon cancer cells by inhibiting the Nrf2 pathway.

[Pathogenesis of benign prostatic hyperplasia from the perspective of syndrome differentiation of viscera based on the neuro-endocrine-immune network].

According to the theory of traditional Chinese medicine (TCM), benign prostatic hyperplasia (BPH) belongs to the category of "Jing Long". Clinical management of BPH in TCM is root-aimed and kidney-targeted, in combination with the treatment of other viscera based on the syndrome differentiation of zang-fu organs. The neuro-endocrine-immune network of modern medicine is similar to the holistic concept of TCM. Based on the study of the neuro-endocrine-immune network, with kidney deficiency as the root of pathogenesis, and starting from the classification of viscera, this review elucidates the etiologic mechanisms of BHP from the perspective of Chinese and Western medicine and provides some reference for medication.

[Characterization and identification of chemical components from Euodiae Fructus based on UHPLC-Q-TOF-MS].

A sensitive and efficient ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) approach was established. Based on the self-developed information library, the chemical components from Euodiae Fructus were systematically characterized and identified. The chromatographic separation conditions(e. g., stationary phase,mobile phase, column temperature, and elution gradient) and MS detection conditions(nozzle voltage, capillary voltage, fragmentor,and collision energy) were optimized. Ultimately, an HSS T3 column(2. 1 mm×100 mm, 1. 8 µm) maintained at 35 ℃ was used,and 0. 1% formic acid water-acetonitrile at the flow rate of 0. 4 m L·min~(-1) was used as the mobile phase. Electrospray ionization was adopted to collect the positive and negative ion mass spectrometry data in Auto MS/MS mode. According to the reference compound comparison, fragment ion information interpretation, literature, and retrieval in the self-developed information library, 92 compounds were characterized or derived from the decoction of Euodiae Fructus, including 33 alkaloids, 23 flavonoids, 12 terpenoids, 12phenylpropanoids, and 12 others. Among them, 17 compounds were identified by comparison with the reference compounds, and 11compounds were unreported from Euodiae Fructus. This study realizes the rapid characterization and identification of multi-class chemical components in the decoction of Euodiae Fructus and provides a reference for the studies regarding its effective substances and quality control.

From Centrosymmetry to Noncentrosymmetry: Precise Structural Regulation and Characterization on ZnHPO3·2H2O Polymorphs.

Polymorphs of ZnHPO3·2H2O with centrosymmetry (Cmcm) and noncentrosymmetry (C2) structures were prepared by modified solution evaporation and seed-crystal-induced secondary nucleation methods. In Cmcm-ZnHPO3·2H2O, the zinc atoms are only octahedrally coordinated, while in C2-ZnHPO3·2H2O, they feature both tetrahedral and octahedral coordination. As a result, Cmcm-ZnHPO3·2H2O features a 2D layered structure with lattice water molecules located in the interlayer space, while C2-ZnHPO3·2H2O features a 3D electroneutral framework of tfa topology connected by Zn(1)O4, Zn(2)O6, and HPO3 units. The UV-visible diffuse reflectance spectra associated with Tauc's analyses give a direct bandgap of 4.24 and 4.33 eV for Cmcm-ZnHPO3·2H2O and C2-ZnHPO3·2H2O, respectively. Moreover, C2-ZnHPO3·2H2O exhibits a weak second harmonic generation (SHG) response and a moderate birefringence for phase matching, indicating its potential as a nonlinear optical material. Detailed dipole moment calculation and analysis confirmed that the SHG response mainly derived from the HPO3 pseudo-tetrahedra.

Perioperative and oncologic outcomes of laparoscopic versus open liver resection for combined hepatocellular-cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. METHODS: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. RESULTS: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs. 8.26 days; p value < 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications' incidence or a negative surgical margin rate between the two groups (p value = 0.409 and p value = 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value = 0.700 and p value = 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. CONCLUSION: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.

[Diagnostic efficacy of prostate cancer using targeted biopsy with 6-core systematic biopsy for patients with PI-RADS 5].

OBJECTIVE: To investigate the diagnostic efficacy of targeted biopsy (TBx), systematic biopsy (SBx), TBx+6-core SBx in prostate cancer (PCa) / clinically significant prostate cancer (cs-PCa) for patients with prostate imaging reporting and data system (PI-RADS) score of 5, and thereby to explore an optimal sampling scheme. METHODS: The data of 585 patients who underwent multiparametric magnetic resonance imaging (mpMRI) with at least one lesion of PI-RADS score 5 at Peking University First Hospital from January 2019 to June 2022 were retrospectively analyzed. All patients underwent mpMRI / transrectal ultrasound (TRUS) cognitive guided biopsy (TBx+SBx). With the pathological results of combined biopsy as the gold standard, we compared the diagnostic efficacy of TBx only, SBx only, and TBx+6-core SBx for PCa/csPCa. The patients were grouped according to mpMRI T-stage (cT2, cT3, cT4) and the detection rates of different biopsy schemes for PCa/csPCa were compared using Cochran's Q and McNemar tests. RESULTS: Among 585 patients with a PI-RADS score of 5, 560 (95.7%) were positive and 25(4.3%) were negative via TBx+SBx. After stratified according to mpMRI T-stage, 233 patients (39.8%) were found in cT2 stage, 214 patients (36.6%) in cT3 stage, and 138 patients (23.6%) in cT4 stage. There was no statistically significant difference in the detection rate of PCa/csPCa between TBx+6-core SBx and TBx+SBx (all P>0.999). Also, there was no statistically significant difference in the detection rate of PCa/csPCa between TBx and TBx+SBx in the cT2, cT3, and cT4 subgroups (PCa: P=0.203, P=0.250, P>0.999; csPCa: P=0.700, P=0.250, P>0.999). The missed diagnosis rate of SBx for PCa and csPCa was 2.1% (12/560) and 1.8% (10/549), and that of TBx for PCa and csPCa was 1.8% (10/560) and 1.4% (8/549), respectively. However, the detection rate of TBx+6-core SBx for PCa and csPCa was 100%. Compared with TBx+SBx, TBx and TBx+6-core SBx had a fewer number of cores and a higher detection rate per core (P < 0.001). CONCLUSION: For patients with a PI-RADS score of 5, TBx and TBx+6-core SBx showed the same PCa/csPCa detection rates and a high detection rates per core as that of TBx+SBx, which can be considered as an optimal scheme for prostate biopsy.

[Characterization and identification of chemical components in traditional Chinese medicine Psoraleae Fructus based on UHPLC-Q-TOF-MS].

This study was designed to comprehensively characterize and identify the chemical components in traditional Chinese medicine Psoraleae Fructus by establishing an ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) method in combination with in-house library. The chromatographic separation conditions(stationary phase, column temperature, mobile phase, and elution gradient) and key MS monitoring parameters(capillary voltage, nozzle voltage, and fragmentor) were sequentially optimized via single-factor experiments. A BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) was finally adopted, with the mobile phase consisting of 0.1% formic acid in water(A) and acetonitrile(B) at the flow rate of 0.4 mL·min~(-1) and column temperature of 30 ℃. Auto MS/MS was utilized for data acquisition in both positive and negative ion modes. By comparison with reference compounds, analysis of the MS~2 fragments, in-house library retrieval and literature research, 83 compounds were identified or tentatively characterized from Psoraleae Fructus, including 58 flavonoids, 11 coumarins, 4 terpenoid phenols, and 10 others. Sixteen of them were identified by comparison with reference compounds, and ten compounds may have not been reported from Psoraleae Fructus. This study achieved a rapid qualitative analysis on the chemical components in Psoraleae Fructus, which provided useful reference for elucidating its material basis and promoting the quality control.

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. METHODS: We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. RESULTS: A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts. CONCLUSIONS: The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. LAY SUMMARY: Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.

Application of Multiparametric Magnetic Resonance Imaging to Monitor the Early Antitumor Effect of CuS@GOD Nanoparticles in a 4 T1 Breast Cancer Xenograft Model.

BACKGROUND: We have developed hybrid nanoparticles (NPs) by co-loading copper sulfide (CuS) NPs and glucose oxidase (GOD) (CuS@GOD NPs) to explore their antitumor properties. PURPOSE: To investigate the feasibility of using multiparametric magnetic resonance imaging (MRI) including intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and R2 * mapping to quantitatively assess the early antitumor effect of CuS@GOD NPs. STUDY TYPE: Prospective. ANIMAL MODEL: The orthotopic BALB/c mice 4 T1 breast cancer model. The 4 T1 xenografts in group 1 mice received normal saline, group 2 received CuS@GOD NPs, group 3 received CuS NPs plus laser, and group 4 received CuS@GOD NPs plus laser (n = 28 for each group). FIELD STRENGTH/SEQUENCE: A 3.0 T/IVIM-DWI MRI single-shot echo-planar imaging, R2 * mapping spoiled gradient recalled echo (SPGR) sequence, T2-weighted images (T2WI) and T1-weighted images (T1WI) fast spin echo (FSE) sequence. ASSESSMENT: The IVIM-DWI and R2 * mapping were performed before and after treatment at 0 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, and 24 hours in four groups and the MRI parameters were obtained. Correlation analysis between the MRI parameters and histological analyses was conducted. STATISTICAL TESTS: One-way ANOVA, Pearson's correlation analysis, two independent samples t test, intraclass correlation coefficient. P < 0.05 was considered to be statistically significant. RESULTS: In group 4, the tumoral D value was significantly higher than that of group 2 at 24 hours (0.541 ± 0.065 vs. 0.492 ± 0.051). The f value of group 4 was significantly lower than that of groups 1 and 2 at 2 hours (10.83 ± 2.16 vs. 14.28 ± 1.86, 16.67 ± 3.53, respectively). The R2 * value was significantly increased at 0 hour in group 4 compared to that of groups 1 and 2 (64.552 ± 4.663 vs. 42.441 ± 1.516, 43.165 ± 1.709, respectively). D, f, and R2 * were correlated with the histological staining results (r = 0.695-0.970). DATA CONCLUSION: The IVIM-DWI-derived D and f and R2 * mapping-derived R2 * could monitor early response to CuS@GOD NPs treatment in vivo. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

LncRNA SNHG1 promotes renal cell carcinoma progression through regulation of HMGA2 via sponging miR-103a.

BACKGROUND: Long noncoding RNAs (LncRNAs) plays a vital role in tumorigenesis and development. The molecular mechanism of SNHG1 in renal cell carcinoma (RCC) has not been illustrated. The aim of this research was to explore the expression and function of LncRNA SNHG1 in RCC. MATERIAL AND METHODS: The expression of SNHG1 in clinical tissues and RCC cell lines was detected. Luciferase reporter assay was performed to verify the correlation between SNHG1, miR-103a, and HMGA2. CCK-8 assay was performed to examine cell viability. Cell apoptosis was analyzed using flow cytometry. Cell invasion capacity was determined by Transwell assays. The protein level of HMGA2 was analyzed by Western blotting. RESULTS: The expression of SNHG1 markedly increased in RCC tissues and cell lines. Subsequent studies identified SNHG1 as a miRNA sponge for miR-103a. In addition, SNHG1 knockdown and miR-103a overexpression significantly inhibited progression of RCC. miR-103a also regulated HMGA2 levels. CONCLUSION: Our findings showed that SNHG1 was upregulated in RCC cells and tissues. SNHG1 promoted the malignant characteristics of RCC cells. Its regulatory effect may be regulation of HMGA2 by sponging miR-103a. Therefore, Our study facilitates the understanding of SNHG1 function in RCC.

Exploring prognostic indicators in the pathological images of hepatocellular carcinoma based on deep learning.

OBJECTIVE: Tumour pathology contains rich information, including tissue structure and cell morphology, that reflects disease progression and patient survival. However, phenotypic information is subtle and complex, making the discovery of prognostic indicators from pathological images challenging. DESIGN: An interpretable, weakly supervised deep learning framework incorporating prior knowledge was proposed to analyse hepatocellular carcinoma (HCC) and explore new prognostic phenotypes on pathological whole-slide images (WSIs) from the Zhongshan cohort of 1125 HCC patients (2451 WSIs) and TCGA cohort of 320 HCC patients (320 WSIs). A 'tumour risk score (TRS)' was established to evaluate patient outcomes, and then risk activation mapping (RAM) was applied to visualise the pathological phenotypes of TRS. The multi-omics data of The Cancer Genome Atlas(TCGA) HCC were used to assess the potential pathogenesis underlying TRS. RESULTS: Survival analysis revealed that TRS was an independent prognosticator in both the Zhongshan cohort (p<0.0001) and TCGA cohort (p=0.0003). The predictive ability of TRS was superior to and independent of clinical staging systems, and TRS could evenly stratify patients into up to five groups with significantly different prognoses. Notably, sinusoidal capillarisation, prominent nucleoli and karyotheca, the nucleus/cytoplasm ratio and infiltrating inflammatory cells were identified as the main underlying features of TRS. The multi-omics data of TCGA HCC hint at the relevance of TRS to tumour immune infiltration and genetic alterations such as the FAT3 and RYR2 mutations. CONCLUSION: Our deep learning framework is an effective and labour-saving method for decoding pathological images, providing a valuable means for HCC risk stratification and precise patient treatment.

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome.

Histone deacetylases 3 (HDAC3) modulates the acetylation state of histone and non-histone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia. Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2-/- stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome.

Bacillus alkalicellulosilyticus sp. nov., isolated from extremely alkaline bauxite residue (red mud) site.

A Gram-stain-negative, rod-shaped, facultatively anaerobic, motile and spore-forming strain designated FJAT-44921T was isolated from red mud collected from Chiping County, Shandong Province, China. The 16S rRNA gene sequence result showed that strain FJAT-44921T shared a low sequence identity (96.6%) with the members of the genus Bacillus. Growth was observed at pH 8.0-10.0 (optimum pH 9.0), 10-40 °C (optimum 20-25 °C) with 0-8% (v/w %) NaCl (optimum 4-6 v/w %). FJAT-44921T consists of MK-7 as the isoprenoid quinone and meso-2,6-diaminopimelic acid as the cell-wall diamino acid. The predominant fatty acids were anteiso-C15:0, iso-C15:0, C16:0, and anteiso-C17:0. The polar lipids were diphosphatidylglycerol, phosphatidyl glycerol, phosphatidylmethylethanolamine, unidentified phospholipid, and unidentified aminophospholipid. The genomic DNA G + C content was 37.3 mol%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between FJAT-44921T and other closely related Bacillus members were lower than the recognized threshold values of ANI (95-96%) and dDDH (70%) recommended as the criterion for interspecies identity. The type strain is FJAT-44921T (=CCTCC AB 2016196T =DSM 104630T).

Laparoscopic hepatectomy enhances recovery for small hepatocellular carcinoma with liver cirrhosis by postoperative inflammatory response attenuation: a propensity score matching analysis with a conventional open approach.

BACKGROUND: The concurrent presence of liver cirrhosis and hepatocellular carcinoma (HCC) poses a challenge for laparoscopic surgeons to establish a routine practice. The aim of this study was to gather evidence and produce recommendations on the safe and effective practice of laparoscopic hepatectomy for patients with solitary HCC (≤ 5 cm) and liver cirrhosis. METHODS: Between October 2013 and October 2014, 356 curative hepatectomies were performed for patients pathologically diagnosed with solitary HCC (≤ 5 cm) accompanied by cirrhosis (stage 4 fibrosis). To overcome selection bias, a 1:2 match using propensity score matching analysis was conducted between laparoscopic and open hepatectomy. Perioperative outcomes were compared between the groups, including hospitalization, operation time, blood loss, and surgical complications. Perioperative inflammation-based markers, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were collected from medical records and analyzed. RESULTS: There were 43 and 77 patients in the laparoscopic and open groups, respectively. The laparoscopic group had less hepatic inflow occlusion (16.3% vs. 61%; P < 0.001), shorter operation time (155 vs. 170 min; P = 0.004), and shorter postoperative hospital stay (4 vs. 7 days; P < 0.001). Although the difference was not significant (P = 0.154), the rate of postoperative complications tended to be lower in the laparoscopic group (2.3%) compared with the open group (9.1%). The increase in postoperative SII, NLR, and LMR for laparoscopic hepatectomy were significantly lower than for open hepatectomy. NLR < 5.8 on postoperative day 3 was significantly correlated with shorter hospital stay (P < 0.001). CONCLUSIONS: Compared with open hepatectomy, laparoscopic hepatectomy for selected HCC patients, even in the presence of cirrhosis, might result in better perioperative outcomes and postoperative inflammatory response attenuation, and ultimately promote faster recovery. This provides evidence for considering routine laparoscopic hepatectomy through careful selection of patients with HCC.

Impact of Radiotherapy on Prognosis in Patients Diagnosed with Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: It has been reported that compared with no local therapy (NLT), patients treated with local therapy (LT) using radiotherapy (RT) possess higher survival rate in metastatic prostate cancer (mPCa). The aim of this meta-analysis was to evaluate the impact of RT on prognosis in patients with mPCa. METHODS: We retrieved the literature in PubMed, Embase, and Cochrane Library databases until June 2019 using structured search terms. Several studies were included, which evaluated patients with mPCa who received RT versus NLT. RESULTS: A total of 14,542 patients were analyzed in 7 included papers (2 randomized controlled trials [RCTs] and 5 cohort retrospective studies [CRS]), and 2,232 mPCa patients were treated with RT and 12,310 with NLT. The data of RCTs and CRS were analyzed separately. In RCTs, RT was associated with no significant difference in overall survival (OS) (pooled hazard ratio [HR] = 0.96; 95% confidence interval [CI]: 0.85-1.09; p = 0.55; I2 = 42%) relative to NLT, while survival benefit was observed in the low-metastatic burden group (pooled HR = 0.68; 95% CI: 0.54-0.86; p = 0.001; I2 = 0%), and no survival benefit was observed in the high-metastatic burden group (pooled HR = 1.07; 95% CI: 0.92-1.24; p = 0.39; I2 = 0%). In CRS, RT results in lower cancer-specific mortality (CSM) (pooled HR = 0.49; 95% CI: 0.34-0.75; p < 0.00001; I2 = 0%) and higher OS (pooled HR = 0.61; 95% CI: 0.55-0.68; p < 0.00001; I2 = 0%) relative to NLT. Subsequent analysis demonstrated that high level of M-stage or N-stage was associated with increased CSM (pooled HR = 2.08; 95% CI: 1.69-2.55; p < 0.00001; I2 = 0% and pooled HR = 1.16; 95% CI: 1.03-1.30; p < 0.00001; I2 = 0%; respectively). CONCLUSIONS: Our observations in aggregate indicated that RT at least does not appear to be harmful and may be beneficial for low-metastatic burden patients and better condition patients. More prospective and randomized studies evaluating RT for mPCa are warranted.

Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.

BACKGROUND & AIMS: The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS: We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. RESULTS: IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). CONCLUSION: Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. LAY SUMMARY: Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma.

Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+ CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal-regulated kinase 1/2, and v-akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor-derived CCR1+ CD14+ monocytes expressed significantly higher levels of programmed cell death-ligand 1, B7-H3, and T-cell immunoglobulin domain and mucin domain-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1+ CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anticancer therapy.

Lymphoid-specific helicase promotes the growth and invasion of hepatocellular carcinoma by transcriptional regulation of centromere protein F expression.

Lymphoid-specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.