Metabolic self-feeding in HBV-associated hepatocarcinoma centered on feedback between circulation lipids and the cellular MAPK/mTOR axis.

INTRODUCTION: Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV- and HBV+ HCC have remained unchanged, limiting HCC treatment options. OBJECTIVES: In this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression. METHODS: We employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes. RESULTS: Our multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients' serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids. CONCLUSION: Our findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.

Ultrastiff metamaterials generated through a multilayer strategy and topology optimization.

Metamaterials composed of different geometrical primitives have different properties. Corresponding to the fundamental geometrical forms of line, plane, and surface, beam-, plate-, and shell-based lattice metamaterials enjoy many advantages in many aspects, respectively. To fully exploit the advantages of each structural archetype, we propose a multilayer strategy and topology optimization technique to design lattice metamaterial in this study. Under the frame of the multilayer strategy, the design space is enlarged and diversified, and the design freedom is increased. Topology optimization is applied to explore better designs in the larger and diverse design space. Beam-plate-shell-combined metamaterials automatically emerge from the optimization to achieve ultrahigh stiffness. Benefiting from high stiffness, energy absorption performances of optimized results also demonstrate substantial improvements under large geometrical deformation. The multilayer strategy and topology optimization can also bring a series of tunable dimensions for lattice design, which helps achieve desired mechanical properties, such as isotropic elasticity and functionally grading material property, and superior performances in acoustic tuning, electrostatic shielding, and fluid field tuning. We envision that a broad array of synthetic and composite metamaterials with unprecedented performance can be designed with the multilayer strategy and topology optimization.

Oncolytic adenovirus in treating malignant ascites: A phase II trial and longitudinal single-cell study.

Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5-73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8+ T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6+ and GZMK+CD8+ T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A+ dendritic cells and GZMK+CD8+ T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular processes following oncolytic virotherapy.

Exploring the efficacy and safety of drug-eluting beads transarterial chemoembolization in pancreatic cancer liver metastasis.

OBJECTIVES: Drug-eluting beads transarterial chemoembolization (DEB-TACE) has shown promise as a treatment modality for primary liver cancer and colorectal cancer liver metastasis. However, its role in pancreatic cancer liver metastasis (PCLM) remains uncertain. This study aimed to investigate the efficacy and safety of DEB-TACE in PCLM patients. METHODS: A retrospective study included 10 PCLM patients who underwent DEB-TACE using CalliSpheres® microspheres as the chemoembolization material. Treatment response, survival outcomes, adverse events, and liver function indexes were comprehensively assessed. RESULTS: Among the patients, complete response, partial response, stable disease, and progressive disease rates were 0.0%, 40.0%, 30.0%, and 30.0%, respectively. The objective response rate was 40.0%, and the disease-control rate was 70.0%. The median progression-free survival (PFS) was 12.0 months (95% CI: 0.0-26.7), with a 1-year PFS rate of 48.0%. The median overall survival (OS) was 18.0 months (95% CI: 6.0-30.0), with a 1-year OS rate of 80.0%. Additionally, no significant differences were observed in any of the liver function indexes, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, etc., between pre- and posttreatment evaluations. Adverse events included pain, grade 1-2 vomiting, fever, and transient liver dysfunction. CONCLUSIONS: DEB-TACE demonstrates a promising treatment response, favorable survival profile, and satisfactory safety in PCLM patients. ADVANCES IN KNOWLEDGE: This study adds to the current research by providing novel evidence on the efficacy, safety, and favorable survival outcomes of DEB-TACE in treating PCLM, highlighting its potential as an effective therapeutic option in this specific population.

Potent induction of antitumor immunity by combining cryo-thermal ablation with immune checkpoint inhibitors in hepatocellular carcinoma.

BACKGROUND: The low response rate of immune checkpoint inhibitors (ICIs) prompts the exploration of novel combination therapies for patients with hepatocellular carcinoma (HCC). Here, we aimed to examine the efficiency and potential mechanism of cryo-thermal ablation (Cryo-A) combined with anti-programmed death protein 1 (αPD1) and/or cytotoxic T-lymphocyte antigen 4 (αCTLA4) inhibitors in a murine hepatoma model. METHOD: Immunocompetent C57BL/6 mice inoculated with unilateral or bilateral H22 hepatic tumour cells were treated with Cryo-A and/or ICIs (αPD1 and/or αCTLA4). Flow cytometry, immunohistochemistry, ELISpot assay, time-of-flight cytometry, tumour rechallenging, and T-cell depletion assay were used to assess the dynamic changes of immune cell subsets following therapy. RESULTS: We found Cryo-A resulted in immunogenic cell death of tumour cells, activation of dendritic cells, and enhancement of antitumor immunity. Cryo-A alone was insufficient to extend survival, combining Cryo-A with αPD1 and αCTLA4 further modulated the tumour microenvironment, inducing a durable antitumor immune response by tumour-reactive CD8+ T cells and significantly prolonged survival. Time-of-flight cytometry (CyTOF) data revealed that combination therapies reshaped the tumour microenvironment by the increase of intratumoral CD8+ T cells expressed higher levels of cytotoxic markers and immune checkpoint molecules, and by downregulation of intratumoral granulocytes. The combination also resulted in the eradication of remote unablated tumours (abscopal effect). CONCLUSIONS: These findings suggested that Cryo-A turned HCC from "cold" tumours to "hot" tumours and the combination of Cryo-A with αPD1 and αCTLA4 may be a promising approach to improve the prognosis of HCC.

Long-lasting complete response to SHR-1701 plus famitinib in refractory advanced gallbladder cancer: A case report.

Biliary tract cancer (BTC) is an aggressive malignancy with few options for advanced-stage treatment. The combination of PD-1/PD-L1 inhibitors with famitinib, a receptor tyrosine kinase (RTK) inhibitor, has demonstrated improved clinical outcomes in several clinical trials. We herein reported a case of a gallbladder cancer (GBC) patient with liver metastases, previously resistant to traditional chemotherapy. Remarkably, the patient achieved a complete response (CR) with a long-lasting survival benefit exceeding 3 years. This was achieved using a novel regimen combining SHR-1701, an anti-PD-L1/TGF-ßR fusion protein, and famitinib, even though the patient had proficient mismatch repair (pMMR) and tested negative for PD-L1. Adverse events were limited and manageable. This is the first report of such a treatment regimen being applied in a clinical setting, suggesting that the SHR-1701 and famitinib combination may be a promising immunotherapeutic approach for patients with refractory advanced GBC.

Brief Change in Dopamine Activity during Consolidation Impairs Long-Term Memory via Sleep Disruption.

Sleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, we show that brief activation of protocerebral anterior medial DANs (PAM-DANs) or inhibition of a pair of dorsal posterior medial (DPM) neurons during the first few hours of memory consolidation impairs 24 h LTM. Interestingly, sleep deprivation elevates the neural activity of PAM-DANs and DPM neurons, and brief thermos-activation of PAM-DANs or inactivation of DPM neurons results in sleep loss and fragmentation. Pharmacological rescue of sleep after this manipulation restores LTM. A specific subset of PAM-DANs, PAM-α1 that synapse onto DPM neurons specify the microcircuit that links sleep and memory. PAM-DANs, including PAM-α1, form functional synapses with DPM neurons mainly via Dop1R1 receptor to inhibit DPM. Our data suggest that the post-training activity of PAM(-α1)-DPM microcircuit, especially during memory consolidation, plays an essential role in maintaining the sleep necessary for LTM consolidation, providing a new cellular and circuit basis for the complex relationship between sleep and memory.

Sequential high-intensity focused ultrasound treatment combined with chemotherapy for inoperable pancreatic cancer: a retrospective analysis for prognostic factors and survival outcomes.

OBJECTIVE: To evaluate the effect of HIFU (High-Intensity Focused Ultrasound) therapy on the survival and prognosis of patients with inoperable pancreatic cancer, and the clinical application of serological prognostic indicators. METHODS: We retrospectively analyzed the clinicopathological features, laboratory tests and follow-ups of 192 patients. Among the patients, 57 were treated with HIFU prior to chemotherapy (HIFU-priority), and 135 patients received chemotherapy followed by HIFU (HIFU-second). Univariate and multivariate Cox regression analysis was used to determine the prognostic value of tumor inflammation-related serological markers. A nomogram model was established based on the identified prognostic factors. RESULTS: Univariate analysis showed that receiving the treatment regimen in HIFU-priority was a significant protective factor for overall survival (OS, p < 0.001). Tumor stage, high C-reactive protein (CRP), high gamma-glutamyl transferase(γGT) high carbohydrate antigen 125 (CA125), high neutrophil-to-lymphocyte ratio (NLR), high lymphocyte-to-monocyte ratio (LMR) and liver metastasis were significant risk factors for poor prognosis (p < 0.05). CRP combined with normal tumor marker CA125 (CRP + CA125) was associated with longer OS (p = 0.005). Multivariate analysis shows that HIFU-priority is a protective factor for OS (Hazard Ratio, HR: 0.38; 95% confidence interval(CI): 0.25-0.57), tumor stage (HR: 1.61; 95% CI: 1.12-2.31), CRP + CA125 (HR: 1.46; 95% CI: 1.02-2.08) and γGT (HR: 1.44; 95% CI: 1.04-1.98) are risk factors for OS and serve as independent prognostic factors in the nomogram. CONCLUSION: Early application of HIFU treatment improves the OS of patients with inoperable pancreatic cancer. CRP + CA125 and γGT are independent prognostic factors.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Case Report: Overcoming challenges in pancreatic cancer with liver metastases: a personalized therapeutic odyssey of TACE, ablation, and immunotherapy.

Pancreatic cancer represents a malignant neoplasm originating from pancreatic cells. The optimal approach to cancer treatment remains uncertain, lacking a definitive consensus. Here, we present a compelling case of a 49-year-old female with pancreatic head cancer with liver metastases, as identified by CT and confirmed by biopsy. PET-CT indicated widespread metastatic involvement. TACE therapy with gemcitabine and cisplatin was initiated, yielding a stable disease response. The patient's high PD-L1 expression prompted TACE-PD-1 monoclonal antibody combination therapy. Subsequent treatments, including ablation, sustained PD-1 immunotherapy, and consolidation TACE, culminated in a complete response, as evidenced by imaging and tumor marker dynamics. Our case underscores the potential of multifaceted strategies in managing aggressive pancreatic cancer.

Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. Trial Registration: ClinicalTrials.gov Identifier: NCT03412773.

Transarterial chemoembolization plus lenvatinib with or without a PD-1 inhibitor for advanced and metastatic intrahepatic cholangiocarcinoma: a retrospective real-world study.

OBJECTIVES: Most patients with intrahepatic cholangiocarcinoma (ICC) present with locally advanced or metastatic disease. We report the combined potency of transarterial chemoembolization (TACE), lenvatinib and programmed cell death-1 (PD-1) inhibitors in patients with advanced and metastatic ICC. METHODS: This retrospective study enrolled 32 patients with advanced or metastatic ICC between January 2017 and August 2021. Eligible patients had received gemcitabine-based TACE combined with lenvatinib with or without PD-1 inhibitor in any line of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Risk factors associated with OS were assessed using univariate and multivariate Cox regression analyses. RESULTS: Eighteen patients received a combination of TACE and lenvatinib (TL group) and 14 patients received TACE and lenvatinib plus aPD-1 inhibitor (TLP group). The median follow-up time was 19.8 months (range 1.8-37.8). The median OS was 25.3 months (95% CI 18.5-32.1) and the median PFS was 7.3 months (95% CI 4.9-9.7). Partial response was achieved in 10 patients (31.3%), and stable disease in 13 (40.6 %) with disease control rate of 71.9%. The median OS was comparable in the TL and TLP groups (22.4 vs 27.3 months, respectively; hazard ratio: 1.245, 95% CI 0.4245-3.653; p = 0.687). The regression analysis revealed that, regardless of treatment group, a favorable independent prognostic factor for OS was HBV/HCV infection (HR: 0.063, 95% CI 0.009-0.463; p = 0.007). There were no treatment-related deaths and 81.3% of study participants experienced adverse events (AEs), the majority of which were of moderate severity (71.8% Grade 1-2). CONCLUSIONS: Gemcitabine-based TACE plus lenvatinib with or without aPD-1 inhibitor was well tolerated and provided promising therapeutic outcomes for patients with advanced and metastatic ICC. ADVANCES IN KNOWLEDGE: Monotherapy with TACE, or Lenvatinib, or PD-1 inhibitors has shown limited efficacy over standard first-line chemotherapy in advanced and metastatic ICC. This work suggested the combined potency of these treatments and well-tolerance.

Quantification of Non-Motor Symptoms in Parkinsonian Cynomolgus Monkeys.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that features motor and non-motor deficits. The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neuron degeneration has been widely practiced to produce reliable animal models of PD. However, most previous preclinical studies focused on motor dysfunction, and few non-motor symptoms were evaluated. Thus far, there is a lack of comprehensive investigations of the non-motor symptoms in animal models. OBJECTIVES: In this study, we aim to use a battery of behavioral methods to evaluate non-motor symptoms in MPTP-induced non-human primate PD models. METHODS: Cognitive function, sleep, and psychiatric behaviors were evaluated in MPTP-treated cynomolgus monkeys. The tests consisted of a delayed matching-to-sample (DMTS) task, the use of a physical activity monitor (PAM), an apathy feeding task (AFT), the human intruder test (HIT), novel fruit test (NFT), and predator confrontation test (PCT). In addition, we tested whether the dopamine receptor agonist pramipexole (PPX) can improve these non-motor symptoms. RESULTS: The present results show that the MPTP-treated monkeys exhibited cognitive deficits, abnormal sleep, and anxiety-like behaviors when compared to the control monkeys. These symptoms were relieved partially by PPX. CONCLUSIONS: These results suggest that MPTP-induced PD monkeys displayed non-motor symptoms that were similar to those found in PD patients. PPX treatment showed moderate therapeutic effects on these non-motor symptoms. This battery of behavioral tests may provide a valuable model for future preclinical research.

Unresectable hepatocellular carcinoma: transarterial chemoembolisation plus Huachansu - a single-center randomised controlled trial.

OBJECTIVE: Huachansu, a Chinese medicine derived from the dried skin glands of toad venom, has been used in China since the 1970s to treat liver cancer. Transarterial chemoembolisation (TACE) is the standard of care for patients with unresectable hepatocellular carcinoma (HCC). This study evaluated the efficacy and safety of the combination of TACE and Huachansu in unresectable HCC. METHODS: From September 2012 to September 2016, 120 patients diagnosed with unresectable HCC were prospectively enrolled. Patients were randomised at a 1:1 ratio into the combined treatment group (Huachansu-TACE) and the TACE treatment group. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and safety. The exploration outcome serum Na+/K+-ATPase (NKA) α3 at baseline and 3-month follow-ups were compared for a prognostic role. All patients were subjected to 36-month follow-up. RESULTS: A total of 112 patients who completed the study were included in the analysis. PFS and OS were significantly better in the Huachansu-TACE group than in the TACE group (p=0.029 and p=0.025, respectively), with a median PFS of 6.8 and 5.3; and a median OS of 14.8 months and 10.7 months, respectively. Although no prognostic significance was found between the baseline NKA-low and NKA-high groups in the patients' OS (p=0.48), its changes after 3-month follow-up showed significant prognostic values, of which, were 8.5 months and 23.8 months, respectively (p<0.001). Treatment-related adverse events were comparable between groups. CONCLUSIONS: Huachansu-TACE is effective in prolonging the PFS and OS in patients with unresectable HCC. TRIAL REGISTRATION NUMBER: NCT01715532.

Non-Hermitian topology in static mechanical metamaterials.

The combination of broken Hermiticity and band topology in physical systems unveils a novel bound state dubbed as the non-Hermitian skin effect (NHSE). Active control that breaks reciprocity is usually used to achieve NHSE, and gain and loss in energy are inevitably involved. Here, we demonstrate non-Hermitian topology in a mechanical metamaterial system by exploring its static deformation. Nonreciprocity is introduced via passive modulation of the lattice configuration without resorting to active control and energy gain/loss. Intriguing physics such as the reciprocal and higher-order skin effects can be tailored in the passive system. Our study provides an easy-to-implement platform for the exploration of non-Hermitian and nonreciprocal phenomena beyond conventional wave dynamics.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Encoding and Storage of Information in Mechanical Metamaterials.

Information processing using material's own properties has gained increasing interest. Mechanical metamaterials, due to their diversity of deformation modes and wide design space, can be used to realize information processing, such as computing and storage. Here a mechanical metamaterial system is demonstrated for material-based encoding and storage of data through programmed reconfigurations of the metamaterial's structured building blocks. Sequential encoding and decoding are achieved in the three-dimensional (3D) printed pixelated mechanical metamaterial via kirigami-based "pixels" with programmable, temperature-dependent bistability. The mechanical metamaterial is demonstrated via a multistep deformation of encoding messages of texts and surfaces with arrays of binary data, and then decoding them by applying a predetermined stretching and heating regimen to sequentially retrieve layers of stored information and display them on its surface. This approach serves as a general framework to enable the encoding and storage of data with mechanical metamaterials.

SDF-1α promotes subchondral bone sclerosis and aggravates osteoarthritis by regulating the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: Subchondral bone sclerosis is a major feature of osteoarthritis (OA), and bone marrow mesenchymal stem cells (BMSCs) are presumed to play an important role in subchondral bone sclerosis. Accumulating evidence has shown that stromal cell-derived factor-1α (SDF-1α) plays a key role in bone metabolism-related diseases, but its role in OA pathogenesis remains largely unknown. The purpose of this study was to explore the role of SDF-1α expressed on BMSCs in subchondral bone sclerosis in an OA model. METHODS: In the present study, C57BL/6J mice were divided into the following three groups: the sham control, destabilization of the medial meniscus (DMM), and AMD3100-treated DMM (DMM + AMD3100) groups. The mice were sacrificed after 2 or 8 weeks, and samples were collected for histological and immunohistochemical analyses. OA severity was assessed by performing hematoxylin and eosin (HE) and safranin O-fast green staining. SDF-1α expression in the OA model was measured using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (q-PCR), and immunohistochemistry. Micro-CT was used to observe changes in subchondral bone in the OA model. CD44, CD90, RUNX2, and OCN expression in subchondral bone were measured using q-PCR and immunohistochemistry. In vitro, BMSCs were transfected with a recombinant lentivirus expressing SDF-1α, an empty vector (EV), or siRNA-SDF-1α. Western blot analysis, q-PCR, and immunofluorescence staining were used to confirm the successful transfection of BMSCs. The effect of SDF-1α on BMSC proliferation was evaluated by performing a CCK-8 assay and cell cycle analysis. The effect of SDF-1α on the osteogenic differentiation of BMSCs was assessed by performing alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Cyclin D1, RUNX2 and OCN expression were measured using Western blot analysis, q-PCR, and immunofluorescence staining. RESULTS: SDF-1α expression in the DMM-induced OA model increased. In the DMM + AMD3100 group, subchondral bone sclerosis was alleviated, OA was effectively relieved, and CD44, CD90, RUNX2, and OCN expression in subchondral bone was decreased. In vitro, high levels of SDF-1α promoted BMSC proliferation and increased osteogenic differentiation. Cyclin D1, RUNX2, and OCN expression increased. CONCLUSION: The results of this study reveal a new molecular mechanism underlying the pathogenesis of OA. The targeted regulation of SDF-1α may be clinically effective in suppressing OA progression.

Single-cell transcriptome analysis revealed the immune profile of PD-1 blockade in gallbladder carcinoma liver metastasis.

BACKGROUND: Gallbladder carcinoma is the most common cancer of the biliary tract, and the immune checkpoint blockade showed promising efficacy in the treatment of advanced gallbladder carcinoma. However, the underlying mechanisms remain unknown. METHODS: Single-cell RNA sequencing was used to reveal immune cell dynamics in an anti-PD-1 responder with gallbladder carcinoma liver metastases. Gene set variation analysis, pseudotime analysis, single-cell regulatory network inference and clustering analysis, and CellChat analysis were used to identify the functions of each cell cluster. Immunohistochemistry and multicolored immunohistochemistry analysis were applied to confirm the intratumoral cell types, and the prognostic value of CXCL13+CD8+T cells in patients with gallbladder carcinoma liver metastases with immunotherapy was evaluated. Four biliary tract carcinoma and 3 immunotherapy bulk RNA-seq datasets were analyzed to investigate the prognostic value of CXCL13+CD8+T cells and SPP1+TAMs. RESULT: A total of 19,648 high-quality single-cell transcriptome data were obtained from liver metastasis before and after aPD-1 therapy. We discovered improved cytotoxic activity in CD8+T cells and enhanced proinflammatory phenotypes in myeloid cells. The identified SPP1+TAMs were related to poor prognosis. The increased effector/memory T cells represented characteristics similar to exhausted T cells in transitory status after aPD-1therapy, which may play a crucial role in the antitumor immune response. We further revealed that CXCL13+T cells in a high subtype of biliary tract carcinoma were characterized as a 'hot tumor' profile with high immune scores, correlated to the immunostimulatory context with favorable survival, and can predict effective responses to immunotherapy. CONCLUSIONS: Our study provided an overview of immune cell dynamics in gallbladder carcinoma liver metastases after aPD-1 treatment and highlighted the importance of CXCL13+T cells in biliary tract carcinoma and effective responses to immunotherapy, which would advance the understanding and treatment of the disease.