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Abstract Background Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. Methods In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM’s effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. Results We defined “a pro-tumor cirrhotic-ECM” which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors’ institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. Conclusions Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

BackgroundThis study evaluates the efficacy of alpha-fetoprotein (AFP) response as a surrogate marker for determining recurrence-free survival (RFS) in patients with unresectable hepatocellular carcinoma (uHCC) who undergo salvage hepatectomy following conversion therapy with tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody-based regimen.MethodsThis multicenter retrospective study included 74 patients with uHCC and positive AFP (>20 ng/mL) at diagnosis, who underwent salvage hepatectomy after treatment with TKIs and anti-PD-1 antibody-based regimens. The association between AFP response—defined as a ≥ 80% decrease in final AFP levels before salvage hepatectomy from diagnosis—and RFS post-hepatectomy was investigated.ResultsAFP responders demonstrated significantly better postoperative RFS compared to non-responders (P

Tidal disruption events (TDE) occur when a star ventures too close to a massive black hole. In a partial TDE (pTDE), the star only grazes the tidal radius, causing the outer envelope of the star to be stripped away while the stellar core survives. Previous research has shown that a star, once tidally stripped in a parabolic orbit, can acquire enough orbital energy for its remnant to become a high-velocity star potentially capable of escaping the galaxy. Conversely, some studies have reported that the remnant may lose orbital energy and undergo re-disruption, leading to a recurring pTDE. This study aims to uncover the physical mechanisms and determine the conditions that lead to these divergent outcomes. We find that the orbital energy change only depends on the impact factor and the stellar structure, and barely depends on the mass of the black hole or the exact mass or orbital eccentricity of the star. For a γ = 5/3 (or γ = 4/3) polytropic star, after a pTDE its remnant gains orbital energy when the impact factor β ≳ 0.62 (or ≳1.1) or loses energy and vice versa. Additionally, we verify an analytical equation for orbital energy change that is applicable across various systems. Through hydrodynamic simulations, we also explore the structure of the stellar remnant post-tidal stripping. Our findings provide critical insights for interpreting observed pTDEs and advancing knowledge on the orbital evolution and event rate of these events.

Background Tertiary lymphoid structures (TLSs) have been proposed to assess the prognosis of patients with cancer. Here, we investigated the prognostic value and relevant mechanisms of TLSs in colorectal cancer liver metastases (CRCLM).Methods 603 patients with CRCLM treated by surgical resection from three cancer centers were included. The TLSs were categorized according to their anatomic subregions and quantified, and a TLS scoring system was established for intratumor region (T score) and peritumor region (P score). Differences in relapse-free survival (RFS) and overall survival (OS) between groups were determined. Multiplex immunohistochemical staining (mIHC) was used to determine the cellular composition of TLSs in 40 CRCLM patients.Results T score positively correlated with superior prognosis, while P score negatively associated with poor survival (all p

Abstract Tumor metastasis is a hallmark of cancer. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated pre-metastatic niche formation during colorectal cancer (CRC) liver metastasis remain incompletely understood. Here we identified HSPC111 was the leading upregulated gene in hepatic stellate cells (HSCs) incubated with CRC cell-derived exosomes. In xenograft mouse model, CRC cell-derived exosomal HSPC111 facilitated pre-metastatic niche formation and CRC liver metastases (CRLM). Consistently, CRC patients with liver metastasis had higher level of HSPC111 in serum exosomes, primary tumors and cancer-associated fibroblasts (CAFs) in liver metastasis than those without. Mechanistically, HSPC111 altered lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulated the level of acetyl-CoA. The accumulation of acetyl-CoA further promoted CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforced exosomal HSPC111 excretion from CRC cells and promoted liver metastasis. These results uncovered that CRC cell-derived exosomal HSPC111 promotes pre-metastatic niche formation and CRLM via reprogramming lipid metabolism in CAFs, and implicate HSPC111 may be a potential therapeutic target for preventing CRLM.

During the inspiralling of a white dwarf (WD) into an intermediate-mass black hole (∼10 ^2−5 M _⊙ ), both gravitational waves (GWs) and electromagnetic (EM) radiation are emitted. Once the eccentric orbit’s pericenter radius approaches the tidal radius, the WD would be tidally stripped upon each pericenter passage. The accretion of this stripped mass would produce EM radiation. It is suspected that the recently discovered new types of transients, namely the quasiperiodic eruptions and the fast ultraluminous x-ray bursts, might originate from such systems. Modeling these flares requires a prediction of the amount of stripped mass from the WD and the details of the mass supply to the accretion disk. We run hydrodynamical simulations to study the orbital parameter dependence of the stripped mass. We find that our results match the analytical estimate that the stripped mass is proportional to z ^5/2 , where z is the excess depth by which the WD overfills its instantaneous Roche lobe at the pericenter. The corresponding fallback rate of the stripped mass is calculated, which may be useful in interpreting the individual flaring light curve in candidate EM sources. We further calculate the long-term mass-loss evolution of a WD during its inspiral and the detectability of the GW and EM signals. The EM signal from the mass-loss stage can be easily detected: the limiting distance is ∼320( M _h /10 ^4 M _⊙ ) Mpc for the Einstein Probe. The GW signal, for space-borne detectors such as Laser Interferometer Space Antenna or TianQin, can be detected only within the Local Supercluster (∼33 Mpc).

Abstract Background The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. Methods The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. Results NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. Conclusions NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

With the rapid development of China's economy and society, the quality of life of residents has continued to improve, and the concept of health has gradually taken root in the hearts of the people. This paper uses the 2018 data of the China Family Panel Studies (CFPS) to analyze the internal mechanism and influencing factors of participating in physical exercise on the health level of residents. The results show that participating in physical exercise can significantly improve the subjective and objective health level of residents, and the result passed two important robustness tests. Heterogeneous test shows that the degree of influence of participation in physical exercise on the health level of residents varies according to the different regional and individual characteristics; the effect of urban residents' physical exercise to improve their health level is better than that of rural residents; and the effect of physical exercise on the improvement of health level is more obvious in the eastern and western areas, those who have not completed compulsory education, and those with high incomes. This study will have strong guiding significance for the improvement of the overall level of national health in China and will provide a theoretical basis and guiding opinions for the construction of healthy China.

Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

Surface heterogeneity significantly influences the properties of porous materials, but remains extremely difficult to characterize. Here, the authors extend Porod’s scattering law from homogeneous to heterogeneous porous materials, allowing for surface variation to be non-invasively probed.

Background: Osteopontin (OPN) is highly expressed in colorectal cancer (CRC) and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy. Methods: HCT116 cell proliferation, apoptosis, and migration and invasion ability were identified by cell counting k¡t-8 assay, flow cytometry, wound healing assay, and transwell chamber invasion assay, respectively. The ratios of proteins LC3-II/LC3-I, P62, and Atg7 were analyzed by Western-blot. Expressions of Beclin-1, Atg4b, Bnip3, and Vps34, both in transcriptional and translational levels, were analyzed and compared by RT-PCR and Western blot. Immunofluorescence and co-focusing experiments were used to investigate the formation of autophagosomes. Results: The results showed that OPN can promote cell proliferation, migration, and invasion, as well as inhibit cell apoptosis. It was also demonstrated that OPN could inhibit cell autophagy. Further experiments revealed that the inhibitory effect of OPN on autophagy could be reversed by blocking the p38 MAPK pathway in HCT116 cells. Conclusion: OPN is involved in HCT116 cell progression and is capable of inhibiting cell autophagy possibly by activating the p38 MAPK signaling pathway, implying that OPN could be a potential novel molecular therapeutic biomarker in patients with CRC.

Background. Soil contamination by hexavalent chromium is becoming a main environmental concern in China. This study developed a sewage sludge biochar modified by FeSO4 (CHBC) as a new reductant for Cr(VI)-contaminated soil. The effectiveness of CHBC-stabilized Cr(VI)-contaminated soil was investigated. Methods. Typical industrial Cr(VI)-contaminated soil in China was chosen as the medium. The total and Cr(VI) contents of the contaminated soil were 1014.6 and 973.5 mg/kg, respectively. The effectiveness of the Cr(VI)-contaminated soil stabilized by CHBC was investigated by the leaching test (US EPA method 1312), the simplified bioaccessibility extraction test (US EPA 2007 protocol and British Geological Survey), alkaline digestion (US EPA method 3060A), sequential extraction (BCR sequential extraction procedure), X-ray diffraction, and the risk assessment code test. Results. Results show that CHBC substantially reduced the leachability and Cr(VI) content of the contaminated soil. The leachability and content of Cr(VI) were lower than the thresholds of the Environmental Quality Standards of Soil in China for civil reuse and the China Environmental Quality Standards of surface water for civil use when the soil was stabilized with 10% dosage of CHBC. Conclusion. CHBC is highly efficient in stabilizing Cr(VI) and can effectively reduce the leachability and bioavailability of Cr in contaminated soil and thus feasible for stabilizing Cr(VI)-contaminated soil and shows potential for application in the field.

Objective: The expression of B-cell lymphoma 2 (Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With the exception of estrogen-related tumors, androgen-related tumors have shown their characteristics in Bcl-2 expression. In this study, the status of Bcl-2 expression in male hepatocellular carcinoma (HCC) patients was examined to verify the high incidence of HCC in males.Methods: Tumor tissue microarray was used to examine Bcl-2 expression levels in 374 HCC cases including 306 males and 68 females. Kaplan-Meier method, log-rank test, and Cox proportional hazards model were applied to investigate the predictive value of Bcl-2 in HCC patients.Results: Immunohistochemistry analysis showed that male patients with higher Bcl-2 levels had significantly longer median survival time and recurrence time than those with lower levels. However, no significant differences in outcomes were found between different Bcl-2 levels in female patients. When the male patients were stratified into several age points, the level of Bcl-2 expression showed poorer predictive efficiency in the 45–49 and 55–60 age groups in andropause-age patients compared with other age groups. Bcl-2 was an independent prognostic factor for both overall survival (P < 0.0001) and recurrence time (P = 0.0001) in male patients. After excluding male patients in the 45–60 age group, the predictive efficiency was enhanced (n = 147, OS, P = 0.0002, TTR, P < 0.0001).Conclusions: Bcl-2 expression is an independent predictor of survival and recurrence in male HCC. Bcl-2 levels may also be regulated by androgens or androgen receptors in male HCC patients. Bcl-2 levels change and exhibit poor predictive efficiency when androgen levels vary dramatically (andropause age).

Background: Ovarian cancer is the most common cause of gynecological cancer-associated death. Iatrogenic menopause might adversely affect the quality of life and health outcomes in young female cancer survivors. We evaluated whether postoperative hormone replacement therapy (HRT) had a negative influence on the progression-free survival (PFS) of patients with papillary serous ovarian cancer (SOC). Methods: We retrospectively reviewed the medical records of patients with papillary SOC, treated from January 1980 to December 2009, who suffered from menopause with or without HRT. Clinical characteristics of patients were compared between the two groups (HRT and non-HRT). Blood samples were collected from all the participants to detect serum cancer antigen (CA) 125. Hazard ratios with 95% confidential intervals for each variable were calculated by univariable and multivariable conditional Logistic regression analyses. Results: Among 112 identified patients, 31 were HRT users and 81 were not. The two groups did not significantly differ in median age at diagnosis (t = 0.652, P = 0.513), International Federation of Gynecology and Obstetrics (FIGO) stage (χ2 = 0.565, P = 0.754), differentiation (χ2 = 1.728, P = 0.422), resection status (χ2 = 0.070, P = 0.791), relapse (χ2 = 0.109, P = 0.741), chemotherapy course (t = −1.079, P = 0.282), follow-up interval (t = 0.878, P = 0.382), or PFS (t = 0.580, P = 0.562). Median Kupperman score at the onset of HRT was 30.81 and 12.19 after the therapy (t = 3.302, P = 0.001). According to the analysis, the strongest independent variables in predicting PFS were FIGO stage and disease that was not optimally debulked. Conclusions: Postoperative HRT is not a prognostic factor for PFS of patients with papillary SOC. However, multicenter studies are needed to verify and extend our findings.

Objective: To evaluate the technical characteristics and application of mass casualty incident (MCI) primary triage (PT) methods applied in China. Data Sources: Chinese literature was searched by Chinese Academic Journal Network Publishing Database (founded in June 2014). The English literature was searched by PubMed (MEDLINE) (1950 to June 2014). We also searched Official Websites of Chinese Central Government's (http://www.gov.cn/), National Health and Family Planning Commission of China (http://www.nhfpc.gov.cn/), and China Earthquake Information (http://www.csi.ac.cn/). Study Selection: We included studies associated with mass casualty events related to China, the PT applied in China, guidelines and standards, and application and development of the carding PT method in China. Results: From 3976 potentially relevant articles, 22 met the inclusion criteria, 20 Chinese, and 2 English. These articles included 13 case reports, 3 retrospective analyses of MCI, two methods introductions, three national or sectoral criteria, and one simulated field testing and validation. There were a total of 19 kinds of MCI PT methods that have been reported in China from 1950 to 2014. In addition, there were 15 kinds of PT methods reported in the literature from the instance of the application. Conclusions: The national and sectoral current triage criteria are developed mainly for earthquake relief. Classification is not clear. Vague criteria (especially between moderate and severe injuries) operability are not practical. There are no triage methods and research for children and special populations. There is no data and evidence supported triage method. We should revise our existing classification and criteria so it is clearer and easier to be grasped in order to build a real, practical, and efficient PT method.

Background: Osteopontin (OPN) is associated with tumor formation, progression and metastasis, and increased OPN levels have been associated with poor survival in breast cancer. We investigated the mechanisms responsible for OPN activity, and the relationships between OPN expression and clinical parameters in breast cancer. Methods: OPN mRNA and protein levels were compared in malignant and benign breast tumors by polymerase chain reaction (PCR) and immunohistochemistry, respectively, and levels in breast cancer cells were determined by PCR and western blotting. The effects of lentiviral-mediated knockdown of OPN on OPN and αv,β3 integrin expression, cell invasion and migration, autophagy and apoptosis were analyzed in MDA-MB-231 cells. Results: OPN expression increased with aggressiveness of breast cancer phenotype. OPN knockdown inhibited αv,β3 integrin expression in MDA-MB-231 cells, with subsequent inhibition of cell migration and invasion. Knockdown also inhibited the PI3K/Akt/mTOR pathway, promoted expression of the autophagy-related gene products LC3 and Beclin 1, and increased apoptosis. OPN expression was positively associated with tumor grade and lymph node metastasis. Conclusion: These results suggest that knockdown of OPN may inhibit breast cancer metastasis by regulating αv,β3 integrin expression and inducing autophagy and subsequent inhibition of PI3K/Akt/mTOR signaling, thus providing further insights into the complex mechanisms regulating tumor growth and metastasis.

Background: To establish the reference range of the angle between ascending aorta and main pulmonary artery of fetus in the second and third trimester using spatiotemporal image correlation (STIC), and to investigate the value of this angle in prenatal screening of conotruncal defects (CTDs). Materials and Methods: Volume images of 311 normal fetuses along with 20 fetuses with congenital heart diseases were recruited in this cross-sectional study. An offline analysis of acquired volume datasets was carried out with multiplanar mode. The angle between aorta and pulmonary artery was measured by navigating the pivot point and rotating axes and the reference range was established. The images of ascending aorta and main pulmonary artery in fetuses with congenital heart diseases were observed by rotating the axes within the normal angle reference range. Results: The angle between ascending aorta and main pulmonary artery of the normal fetus (range: 59.1˚~97.0˚, mean ± SD: 78.0˚ ± 9.7˚) was negatively correlated with gestational age (r = -0.52; p < 0.01). By rotating the normal angle range corresponding to gestational age, the fetuses with CTD could not display views of their left ventricular long axis and main pulmonary trunk correctly. Conclusion: The left ventricular long axis and main pulmonary trunk views can be displayed using STIC so that the echocardiographic protocol of the cardiovascular joint could be standardized. The reference range of the angle between ascending aorta and main pulmonary artery is clinically useful in prenatal screening of CTD and provides a reliable quantitative standard to estimate the spatial relationship of the large arteries of fetus.

Recently discovered regular X-ray bursts known as quasi-periodic eruptions have a proposed model that suggests a tidal stripping white dwarf inspiralling into the galaxy's central black hole on an eccentric orbit. According to this model, the interaction of the stripping white dwarf with the central black hole would also emit gravitational wave signals, their detection can help explore the formation mechanism of quasi-periodic eruptions and facilitate multimessenger observations. In this paper, we investigated the horizon distance of TianQin on this type of gravitation wave signal and found it can be set to 200 Mpc. We also find that those stripping white dwarf model sources with central black hole mass within |$10^4 \!-\! 10^{5.5}\, \mathrm{M}_\odot$| are more likely to be detected by TianQin. We assessed the parameter estimation precision of TianQin on those stripping white dwarf model sources. Our result shows that, even in the worst case, TianQin can determine the central black hole mass, the white dwarf mass, the central black hole spin, and the orbital initial eccentricity with a precision of 10−2. In the optimistic case, TianQin can determine the central black hole mass and the white dwarf mass with a precision of 10−7, determine the central black hole spin with a precision of 10−5, and determine the orbital initial eccentricity with a precision of 10−8. Moreover, TianQin can determine the luminosity distance with a precision of 10−1 and determine the sky localization with a precision of 10−2–10  |$\rm deg^2$|⁠. [ABSTRACT FROM AUTHOR]

Background: The value of existing prognostic models for intrahepatic cholangiocarcinoma is limited. The inclusion of prognostic gene mutations would enhance the predictive efficacy. Methods: In the screening cohorts, univariable Cox regression analysis was applied to investigate the effect of individual mutant genes on overall survival (OS). In the training set, multivariable analysis was performed to evaluate the independent prognostic roles of the clinicopathological and mutational parameters, and a prognostic model was constructed. Internal and external validations were conducted to evaluate the performance of this model. Results: Among the recurrent mutations, only TP53 and KRASG12 were significantly associated with OS across all three screening cohorts. In the training cohort, TP53 and KRASG12 mutations in combination with seven other clinical parameters (tumor size, tumor number, vascular invasion, lymph node metastasis, adjacent invasion, CA19-9, and CEA), were independent prognostic factors for OS. A mutation-annotated prognostic score (MAPS) was established based on the nine prognosticators. The C-indices of MAPS (0.782 and 0.731 in the internal and external validation cohorts, respectively) were statistically higher than those of other existing models (P <0.05). Furthermore, the MAPS model also demonstrated significant value in predicting the possible benefits of upfront surgery and adjuvant therapy. Conclusions: The MAPS model demonstrated good performance in predicting the OS of intrahepatic cholangiocarcinoma patients. It may also help predict the possible benefits of upfront surgery and adjuvant therapy. [ABSTRACT FROM AUTHOR]