3D trajectories adopted by coding and regulatory DNA elements: first-passage times for genomic interactions.

During B lymphocyte development, immunoglobulin heavy-chain variable (VH), diversity (DH), and joining (JH) segments assemble to generate a diverse antigen receptor repertoire. Here, we have marked the distal VH and DH-JH-Eµ regions with Tet-operator binding sites and traced their 3D trajectories in pro-B cells transduced with a retrovirus encoding Tet-repressor-EGFP. We found that these elements displayed fractional Langevin motion (fLm) due to the viscoelastic hindrance from the surrounding network of proteins and chromatin fibers. Using fractional Langevin dynamics modeling, we found that, with high probability, DHJH elements reach a VH element within minutes. Spatial confinement emerged as the dominant parameter that determined the frequency of such encounters. We propose that the viscoelastic nature of the nuclear environment causes coding elements and regulatory elements to bounce back and forth in a spring-like fashion until specific genomic interactions are established and that spatial confinement of topological domains largely controls first-passage times for genomic interactions.

Proximity to criticality predicts surface properties of biomolecular condensates.

It has recently become appreciated that cells self-organize their interiors through the formation of biomolecular condensates. These condensates, typically formed through liquid-liquid phase separation of proteins, nucleic acids, and other biopolymers, exhibit reversible assembly/disassembly in response to changing conditions. Condensates play many functional roles, aiding in biochemical reactions, signal transduction, and sequestration of certain components. Ultimately, these functions depend on the physical properties of condensates, which are encoded in the microscopic features of the constituent biomolecules. In general, the mapping from microscopic features to macroscopic properties is complex, but it is known that near a critical point, macroscopic properties follow power laws with only a small number of parameters, making it easier to identify underlying principles. How far does this critical region extend for biomolecular condensates and what principles govern condensate properties in the critical regime? Using coarse-grained molecular-dynamics simulations of a representative class of biomolecular condensates, we found that the critical regime can be wide enough to cover the full physiological range of temperatures. Within this critical regime, we identified that polymer sequence influences surface tension predominately via shifting the critical temperature. Finally, we show that condensate surface tension over a wide range of temperatures can be calculated from the critical temperature and a single measurement of the interface width.

Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies.

OBJECTIVES: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. DESIGN: Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. RESULTS: We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. CONCLUSION: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

Development and validation of robust metabolism-related gene signature in the prognostic prediction of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Given metabolic reprogramming in tumours was a crucial hallmark, several studies have demonstrated its value in the diagnostics and surveillance of malignant tumours. The present study aimed to identify a cluster of metabolism-related genes to construct a prediction model for the prognosis of HCC. Multiple cohorts of HCC cases (466 cases) from public datasets were included in the present analysis. (GEO cohort) After identifying a list of metabolism-related genes associated with prognosis, a risk score based on metabolism-related genes was formulated via the LASSO-Cox and LASSO-pcvl algorithms. According to the risk score, patients were stratified into low- and high-risk groups, and further analysis and validation were accordingly conducted. The results revealed that high-risk patients had a significantly worse 5-year overall survival (OS) than low-risk patients in the GEO cohort. (30.0% vs. 57.8%; hazard ratio [HR], 0.411; 95% confidence interval [95% CI], 0.302-0.651; p < 0.001) This observation was confirmed in the external TCGA-LIHC cohort. (34.5% vs. 54.4%; HR 0.452; 95% CI, 0.299-0.681; p < 0.001) To promote the predictive ability of the model, risk score, age, gender and tumour stage were integrated into a nomogram. According to the results of receiver operating characteristic curves and decision curves analysis, the nomogram score possessed a superior predictive ability than conventional factors, which indicate that the risk score combined with clinicopathological features was able to achieve a robust prediction for OS and improve the individualized clinical decision making of HCC patients. In conclusion, the metabolic genes related to OS were identified and developed a metabolism-based predictive model for HCC. Through a series of bioinformatics and statistical analyses, the predictive ability of the model was approved.

A risk-based postresection follow-up strategy for hepatocellular carcinoma patients.

BACKGROUND: The optimal intervals for follow-up after hepatocellular carcinoma (HCC) patients undergo curative liver resection (LR) remain unclear. This study aimed to establish a risk-based post-resection follow-up strategy. METHODS: Patients that were diagnosed with HCC and received LR from three hospitals in China were included. The risk-based strategy was established based on the random survival forest model and compared with a fixed strategy both internally and externally. RESULTS: In total, 3447 patients from three hospitals were included. The authors' strategy showed superiority in the early detection of tumor relapse compared with fixed surveillance. Under fewer total visits, risk-based strategy achieved analogous survival time compared to the total 20 times follow-ups based on fixed strategy. Twelve total visits (five, three, one, two, and one visits in years 1-5, respectively) for American Joint Committee on Cancer/International Union Against Cancer T1a stage patients, 13 total visits (five, four, one, two, and one visits in years 1-5, respectively) for T1b stage patients, 15 total visits (eight, three, three, zero, and one visits in years 1-5, respectively) for T2 stage patients, and 15 total visits (eight, four, one, one, and one visits in years 1-5, respectively) for T3 stage patients were advocated. The detailed follow-up arrangements were available to the public through an interactive website (https://sysuccfyz.shinyapps.io/RiskBasedFollowUp/). CONCLUSION: This risk-based surveillance strategy was demonstrated to detect relapse earlier and reduce the total number of follow-ups without compromising on survival. Based on the strategy and methodology of the authors, surgeons or patients could choose more intensive or flexible schedules depending on the requirements and economic conditions. PLAIN LANGUAGE SUMMARY: A risk-based post-resection follow-up strategy was established by random survival forest model using a larger hepatocellular carcinoma population The strategy was demonstrated to detect tumor relapse earlier and reduce the total number of follow-ups without compromising on survival Our strategy and methodology could be widely applied by other surgeons and patients.

Efficacy and Dose-Response Relationship of Stereotactic Body Radiotherapy for Abdominal Lymph Node Metastases from Hepatocellular Carcinoma.

BACKGROUND: The objective of this study was to investigate the treatment efficacy of stereotactic body radiotherapy (SBRT) and evaluate the influence of radiation dose on local control and survival in patients with abdominal lymph node metastases (LNM) from hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Between 2010 and 2020, data of 148 patients with HCC with abdominal LNM, including 114 who underwent SBRT and 34 who received conventional fractionation radiation therapy (CFRT), were collected. A total radiation dose of 28-60 Gy was delivered in 3-30 fractions, with a median biologic effective dose (BED) of 60 Gy (range, 39-105 Gy). Freedom from local progression (FFLP) and overall survival (OS) rates were analyzed. RESULTS: With a median follow-up of 13.6 months (range, 0.4-96.0 months), the 2-year FFLP and OS rates of the entire cohort were 70.6% and 49.7%, respectively. Median OS of the SBRT group was longer than the CFRT group (29.7 vs. 9.9 months, P = .007). A dose-response relationship was observed between local control and BED in either the entire cohort or the SBRT subgroup. Patients who received SBRT with a BED ≥60 Gy had significantly higher 2-year FFLP and OS rates than those who received a BED <60 Gy (80.1% vs. 63.4%, P = .004; 68.3% vs. 33.0%, P < .001). On multivariate analysis, BED was an independent prognostic factor for both FFLP and OS. CONCLUSIONS: SBRT achieved satisfactory local control and survival with feasible toxicities in patients with HCC with abdominal LNM. Moreover, the findings of this large series suggest a dose-response relationship between local control and BED.

Erratum: Mechanical Frustration of Phase Separation in the Cell Nucleus by Chromatin [Phys. Rev. Lett. 126, 258102 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.258102.

An integrated strategy for deciding open versus laparoscopic hepatectomy for resectable primary liver cancer.

BACKGROUND: Laparoscopic liver resection (LLR) is now widely performed in treating primary liver cancer (PLC) and yields equal long-term and superior short-term outcomes to those of open liver resection (OLR). The optimal surgical approach for resectable PLC (rPLC) remains controversial. Herein, we aimed to develop a nomogram to determine the most appropriate resection approach for the individual patient. METHODS: Patients with rPLC who underwent hepatectomy from January 2013 to December 2018 were reviewed. Prediction model for risky surgery during LLR was constructed. RESULTS: A total of 900 patients in the LLR cohort and 423 patients in the OLR cohort were included. A history of previous antitumor treatment, tumor diameter, tumor location and resection extent were independently associated with risky surgery of LLR. The nomogram which was constructed based on these risk factors demonstrated good accuracy in predicting risky surgery with a C index of 0.83 in the development cohort and of 0.76 in the validation cohort. Patients were stratified into high-, medium- or low-risk levels for receiving LLR if the calculated score was more than 0.8, between 0.2 and 0.8 or less than 0.2, respectively. High-risk patients who underwent LLR had more blood loss (441 ml to 417 ml) and a longer surgery time (183 min to 150 min) than those who received OLR. CONCLUSIONS: Patients classified into the high-risk level for LLR instead undergo OLR to reduce surgical risks and complications and patients classified into the low-risk level undergo LLR to maximize the advantages of minimally invasive surgery. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100049446).

Retrograde percutaneous coronary intervention of chronic total occlusion via discontinuous septal channels.

OBJECTIVES: The study aims to investigate the safety and feasibility of retrograde CTO intervention via collateral connection grade 0 (CC-0) septal channel and to identify predictors of collateral tracking failure. BACKGROUND: Guidewire crossing a collateral channel is a critical step for successful retrograde percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). METHODS: Retrograde PCI was attempted in 122 cases of CTO with CC-0 septal collaterals from December 2018 to May 2021. A hydrophilic polymer coating guidewire was used for crossing all intended CC-0 collaterals. A multivariable logistic regression analysis was performed to identify the predictors of guidewire tracking failure via the CC-0 collaterals. RESULTS: Successful guidewire tracking via CC-0 septal channel was achieved in 98 (80.3%) of 122 cases. The independent predictors of CC-0 septal channel guidewire tracking failure included well-developed non-septal collateral (OR: 5.297, 95% CI: 1.107-25.353, p = 0.037) and the ratio length of posterior descending artery (PDA) versus the distance of PDA ostium to cardiac apex ≤2/3 (OR: 3.970, 95% CI: 1.454-10.835, p = 0.007). Collateral perforation, target vessel perforation, and cardiac tamponade occurred in 5 (4.1%), 3 (2.5%), and 6 (4.9%) cases, respectively. There were no complications requiring emergency cardiac surgery or revascularization of nontarget vessel. CONCLUSIONS: Retrograde PCI via CC-0 septal channels with a hydrophilic polymer-coated guidewire is feasible and safe in patients with CTO. Well-developed nonseptal collaterals and short PDA length influence the procedure success and the risk of guidewire tracking failure via CC-0 septal channels.

Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia.

BACKGROUND: Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI). METHODS: Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM. RESULTS: Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats. CONCLUSIONS: These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI.

Seeing the forest and the trees: Holistic view of social distancing on the spread of COVID-19 in China.

The human social and behavioral activities play significant roles in the spread of COVID-19. Social-distancing centered non-pharmaceutical interventions (NPIs) are the best strategies to curb the spread of COVID-19 prior to an effective pharmaceutical or vaccine solution. This study investigates various social-distancing measures' impact on the spread of COVID-19 using advanced global and novel local geospatial techniques. Social distancing measures are acquired through website analysis, document text analysis, and other big data extraction strategies. A spatial panel regression model and a newly proposed geographically weighted panel regression model are applied to investigate the global and local relationships between the spread of COVID-19 and the various social distancing measures. Results from the combined global and local analyses confirm the effectiveness of NPI strategies to curb the spread of COVID-19. While global level strategies allow a nation to implement social distancing measures immediately at the beginning to minimize the impact of the disease, local level strategies fine tune such measures based on different times and places to provide targeted implementation to balance conflicting demands during the pandemic. The local level analysis further suggests that implementing different NPI strategies in different locations might allow us to battle unknown global pandemic more efficiently.

Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Compared with visual angiographic assessment, pressure wire-based physiological measurement more accurately identifies flow-limiting lesions in patients with coronary artery disease. Nonetheless, angiography remains the most widely used method to guide percutaneous coronary intervention (PCI). In FAVOR III China, we aimed to establish whether clinical outcomes might be improved by lesion selection for PCI using the quantitative flow ratio (QFR), a novel angiography-based approach to estimate the fractional flow reserve. METHODS: FAVOR III China is a multicentre, blinded, randomised, sham-controlled trial done at 26 hospitals in China. Patients aged 18 years or older, with stable or unstable angina pectoris or patients who had a myocardial infarction at least 72 h before screening, who had at least one lesion with a diameter stenosis of 50-90% in a coronary artery with a reference vessel of at least 2·5 mm diameter by visual assessment were eligible. Patients were randomly assigned to a QFR-guided strategy (PCI performed only if QFR ≤0·80) or an angiography-guided strategy (PCI based on standard visual angiographic assessment). Participants and clinical assessors were masked to treatment allocation. The primary endpoint was the 1-year rate of major adverse cardiac events, a composite of death from any cause, myocardial infarction, or ischaemia-driven revascularisation. The primary analysis was done in the intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT03656848). FINDINGS: Between Dec 25, 2018, and Jan 19, 2020, 3847 patients were enrolled. After exclusion of 22 patients who elected not to undergo PCI or who were withdrawn by their physicians, 3825 participants were included in the intention-to-treat population (1913 in the QFR-guided group and 1912 in the angiography-guided group). The mean age was 62·7 years (SD 10·1), 2699 (70·6%) were men and 1126 (29·4%) were women, 1295 (33·9%) had diabetes, and 2428 (63·5%) presented with an acute coronary syndrome. The 1-year primary endpoint occurred in 110 (Kaplan-Meier estimated rate 5·8%) participants in the QFR-guided group and in 167 (8·8%) participants in the angiography-guided group (difference, -3·0% [95% CI -4·7 to -1·4]; hazard ratio 0·65 [95% CI 0·51 to 0·83]; p=0·0004), driven by fewer myocardial infarctions and ischaemia-driven revascularisations in the QFR-guided group than in the angiography-guided group. INTERPRETATION: In FAVOR III China, among patients undergoing PCI, a QFR-guided strategy of lesion selection improved 1-year clinical outcomes compared with standard angiography guidance. FUNDING: Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Centre for Cardiovascular Diseases, Fuwai Hospital.

Combined lifestyle, mental health, and mortality in US cancer survivors: a national cohort study.

BACKGROUND: Adopting healthy lifestyles and staying mentally health are two cost-effective modifiable strategies that cancer survivors can implement in self-management. We aimed to evaluate the independent, mediation, interaction, and joint associations of combined lifestyle and mental health with mortality in cancer survivors. METHODS: We performed a cohort study including 3145 cancer survivors from National Health and Nutrition Examination Survey (2005-2018). A healthy lifestyle score was constructed based on post-diagnosis body mass index, physical activity, diet, smoking, and drinking. Post-diagnosis mental health was assessed by Patient Health Questionnaire (PHQ-9). Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cancer, and non-cancer mortality were computed using Cox proportional hazards regression models. RESULTS: After 20,900 person-years of follow-up (median, 6.3 years), cancer survivors with higher lifestyle score had decreased mortality, independent of mental health. Compared to participants with lower lifestyle score (0-1), HRs (95% CIs) for all-cause and non-cancer mortality among those with higher lifestyle score (3-5) were 0.68 (0.52-0.89) and 0.69 (0.56-0.85), respectively. 6.2-10.3% of the associations were mediated by mental health. Similar trends were observed among participants categorized by mental health, those with better mental health had lower mortality, independent of lifestyle. Participants with better mental health benefited more from adopting healthy lifestyles, and vice versa. Combinations of higher healthy lifestyle score and better mental health were associated with significant decreased mortality, the lowest mortality was seen in participants with highest healthy lifestyle score and concurrently with best mental health. CONCLUSIONS: For the first time, in this cohort study with a nationally representative sample of US cancer survivors, we comprehensively explored the complex associations of lifestyle, mental health, and mortality. Evidence derived from this study may give much confidence to cancer survivors and healthcare providers that, changing one's lifestyle and/or staying mentally healthy after cancer diagnosis can improve survival.

Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression.

BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis. APPROACH AND RESULTS: In the HCC-TME, CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-ß secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF-ß secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1-CXCL6/TGF-ß axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis. CONCLUSIONS: This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1-CXCL6/TGF-ß axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.

Comparison Between Portal Vein Perfusion Chemotherapy and Neoadjuvant Hepatic Arterial Infusion Chemotherapy for Resectable Intermediate to Advanced Stage Hepatocellular Carcinoma.

BACKGROUND: Patients with intermediate to advanced stage hepatocellular carcinoma (HCC; Barcelona Clinic Liver Cancer [BCLC] stage B/C) have few choices of curable treatments and thus suffer from dismal outcomes. Although surgical resection could prolong survival in certain selected patients with BCLC stage B/C HCC, the frequent postoperative recurrence and poor survival of these patients need to be improved by combining other therapies perioperatively. OBJECTIVE: This study was conducted to investigate the survival associations of adjuvant portal vein perfusion chemotherapy (PVC) and neoadjuvant hepatic arterial infusion chemotherapy (HAIC) in patients with resectable BCLC stage B/C HCC. METHODS: A retrospective study was conducted in consecutive patients who underwent R0 resection for intermediate to advanced stage HCC, combined with either PVC or HAIC perioperatively between January 2017 and December 2018. Patients treated with PVC or HAIC were analyzed according to intention-to-treat (ITT) and per protocol (PP) principles, respectively. The chemotherapy regimen of adjuvant PVC and neoadjuvant HAIC included 5-fluorouracil/leucovorin/oxaliplatin. Survival analysis and Cox regression for overall survival (OS) and event-free survival (EFS) were used to compare the outcomes. RESULTS: Among all 64 patients enrolled in this study, 28 received perioperative PVC and 36 received HAIC for ITT analysis. Age (median 44.00 vs. 46.50 years; p = 0.364), sex (male: 25/28 vs. 35/36; p = 0.435), and tumor size (median 9.55 vs. 8.10 cm; p = 0.178) were comparable between the two groups. In the ITT analysis, the median OS was significantly longer in patients in the HAIC group compared with the PVC group (median OS not reached vs. 19.47 months; p = 0.004); in the PP analysis, patients who received neoadjuvant HAIC followed by hepatectomy presented with much better EFS than patients in the PVC group (modified EFS 16.90 vs. 3.17 months; p = 0.022); and in the multivariate analysis, neoadjuvant HAIC presented as a significant predictor for enhanced EFS (hazard ratio [HR] 0.296; p = 0.007) and OS (HR 0.095; p = 0.007) for BCLC stage B/C HCC patients who received hepatectomy. CONCLUSIONS: Compared with adjuvant PVC, neoadjuvant HAIC treatment was associated with better survival and fewer recurrences in HCC patients who received R0 resection at the intermediate to advanced stage. These results need to be further validated prospectively.

Stoichiometry Controls the Dynamics of Liquid Condensates of Associative Proteins.

Multivalent associative proteins with strong complementary interactions play a crucial role in phase separation of intracellular liquid condensates. We study the internal dynamics of such "bond-network" condensates comprising two complementary proteins via scaling analysis and molecular dynamics. We find that when stoichiometry is balanced, relaxation slows down dramatically due to a scarcity of alternative binding partners following bond breakage. This microscopic slow-down strongly affects the bulk diffusivity, viscosity, and mixing, which provides a means to experimentally test this prediction.

High serum fibroblast growth factor 21 is associated with inferior hepatocellular carcinoma survival: A prospective cohort study.

BACKGROUND & AIMS: Epidemiological evidence linking fibroblast growth factor 21 (FGF21) with hepatocellular carcinoma (HCC) prognosis lacked. We aimed to evaluate the associations between serum FGF21 levels and HCC survival in a large prospective cohort. METHODS: 825 newly diagnosed, previously untreated HCC patients from the Guangdong Liver Cancer Cohort were enrolled between September 2013 and April 2017. Serum FGF21 levels were measured by ELISA. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Multivariable Cox proportional hazards models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Compared with patients in the lowest tertile of serum FGF21 levels, patients in the highest tertile had inferior survival outcomes. HRs in the fully adjusted models were 1.44 (95% CI: 1.07, 1.94; P-trend  = .014) and 1.48 (95% CI: 1.12, 1.97; P-trend  = .002) for LCSS and OS, respectively. The associations were not significantly modified by selected metabolic disorder diseases or state such as arterial hypertension, diabetes, dyslipidemia, fatty liver, cirrhosis, and body mass index ≥25.0 kg/m2 , except for that stronger associations were observed in patients co-occurred more than three metabolic disorder diseases (P-interaction  = .046 for OS and .151 for LCSS), with an HR of 2.01 (95% CI: 1.04, 3.85; P-trend  = .009) for OS and 1.51 (95% CI: 0.73, 3.10; P-trend  = .195) for LCSS. CONCLUSIONS: Higher serum FGF21 levels were associated with worse survival in HCC patients, suggesting that serum FGF21 may be used as a novel metabolism-related prognostic biomarker for HCC.

The role of neoadjuvant conventional transarterial chemoembolization with radiofrequency ablation in the treatment of recurrent hepatocellular carcinoma after initial hepatectomy with microvascular invasion.

OBJECTIVES: Recurrent hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI)-positive primary tumor is at high risk of re-recurrence while treated with radiofrequency ablation (RFA). We aimed to investigate whether neoadjuvant conventional transarterial chemoembolization (cTACE) was effective in reducing re-recurrence after RFA for recurrent HCC patients with MVI-positive primary tumors. METHODS: In this retrospective multicenter study, 468 patients with solitary small recurrent HCC (≤3.0cm) underwent RFA alone (n = 322) or with neoadjuvant cTACE (n = 146) between June 2007 and December 2017 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared. RESULTS: The 1-, 5-year OS rates were 74.8%, 42.5% for RFA with neoadjuvant cTACE group, and 53.5%, 28.7% for RFA group (P < 0.001). The corresponding RFS rates were 51.7%, 24.4% for RFA with neoadjuvant cTACE group, and 36.1%, 9.3% for RFA group (P < 0.001). In subgroup analyses, the OS and RFS for neoadjuvant cTACE group were longer than those for RFA group no matter tumor size > 2cm (HR = 0.52, 95% CI: 0.36-0.77; HR = 0.49, 95% CI: 0.36-0.67) or not (HR = 0.53, 95% CI: 0.32-0.88; HR = 0.65, 95% CI: 0.42-0.98), or the time interval of recurrence from initial treatment ≤ 1 year (HR = 0.53, 95% CI: 0.36-0.77; HR = 0.70, 95% CI: 0.52-0.94) or not (HR = 0.56, 95% CI: 0.34-0.95; HR = 0.39, 95% CI: 0.25-0.62). Multivariable analyses showed that RFA alone (HR = 1.329, P = 0.031; HR = 1.764, P = 0.004) and interval of recurrence from initial treatment > 1 year(HR = 0.642, P = 0.001; HR = 0.298, P = 0.037) were independent prognostic factors of OS and RFS. CONCLUSIONS: Neoadjuvant cTACE could effectively reduce re-recurrence after RFA, and improve the long-term survivals for patients with solitary small recurrent HCC whose primary tumor was MVI-positive. Key pointsFor recurrent hepatocellular carcinoma (HCC) patients whose primary tumor was positive for microvascular invasion, neoadjuvant conventional transarterial chemoembolization (cTACE) with radiofrequency ablation (RFA) achieved better efficacy.Multivariable analyses showed that the interval of recurrence from initial treatment > 1 year and RFA alone were independent prognostic factors of overall survival and recurrence-free survival, respectively.

Regulation of T cell expansion by antigen presentation dynamics.

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

Comparison of HBV reactivation between patients with high HBV-DNA and low HBV-DNA loads undergoing PD-1 inhibitor and concurrent antiviral prophylaxis.

BACKGROUND: Programmed cell death protein-1 (PD-1) inhibitor is recommended to treat advanced hepatocellular carcinoma (HCC). However, the safety of PD-1 inhibitor in patients with high HBV-DNA load is unknown because of the potential risk of hepatitis B virus (HBV) reactivation. This study was to compare the HBV reactivation between patients with low HBV-DNA loads and high HBV-DNA loads undergoing antiviral prophylaxis and PD-1 inhibitor. METHODS: This was a retrospective study including consecutive hepatitis B surface antigen-positive HCC patients who received PD-1 inhibitor and concurrent antiviral prophylaxis for prevention of clinical hepatitis. Patients were divided into low HBV-DNA group (low group, ≤ 500 IU/ml) and high HBV-DNA group (high group, > 500 IU/ml) according to the baseline HBV-DNA level. The incidences of HBV reactivation, HBV-associated hepatitis, and PD-1 inhibitor disruption were compared between the two groups. RESULTS: Two hundred two eligible patients were included: 94 in the low group and 108 in the high group. Seven patients (5 in the low group and 2 in the high group) developed HBV reactivation, and all recovered from HBV reactivation and HBV-associated hepatitis. The incidence of HBV reactivation in the two groups was low (5.3% vs 1.9%, P = 0.34). There was also no difference in the incidence of HBV-associated hepatitis (P = 0.56), or PD-1 inhibitor disruption (P = 0.82). The multivariable analysis showed PD-1 inhibitor with hepatic arterial infusion chemotherapy was the only significant risk factor for HBV reactivation (P = 0.04) and hepatitis (P = 0.002). CONCLUSION: With concurrent antiviral prophylaxis, HBV-DNA load higher than 500 IU/ml should not be a contraindication for PD-1 inhibitor.