Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Smart patterning for topological pumping of elastic surface waves.

Topological pumping allows waves to navigate a sample undisturbed by disorders and defects. We demonstrate this phenomenon with elastic surface waves by strategically patterning an elastic surface to create a synthetic dimension. The surface is decorated with arrays of resonating pillars that are connected by spatially slow-varying coupling bridges and support eigenmodes located below the sound cone. We establish a connection between the collective dynamics of the pillars and that of electrons in a magnetic field by developing a tight-binding model and a WKB (Wentzel-Kramers-Brillouin) analysis. This enables us to predict the topological pumping pattern, which we validate through numerical and experimental steering of waves from one edge to the other. Furthermore, we observe the immune nature of the topologically pumped surface waves to disorder and defects. The combination of surface patterning and WKB analysis provides a versatile platform for controlling surface waves and exploring topological matter in higher dimensions.

CcRR5 interacts with CcRR14 and CcSnRK2s to regulate the root development in citrus.

Response regulator (RR) is an important component of the cytokinin (CK) signal transduction system associated with root development and stress resistance in model plants. However, the function of RR gene and the molecular mechanism on regulating the root development in woody plants such as citrus remain unclear. Here, we demonstrate that CcRR5, a member of the type A RR, regulates the morphogenesis of root through interacting with CcRR14 and CcSnRK2s in citrus. CcRR5 is mainly expressed in root tips and young leaves. The activity of CcRR5 promoter triggered by CcRR14 was proved with transient expression assay. Seven SnRK2 family members with highly conserved domains were identified in citrus. Among them, CcSnRK2.3, CcSnRK2.6, CcSnRK2.7, and CcSnRK2.8 can interact with CcRR5 and CcRR14. Phenotypic analysis of CcRR5 overexpressed transgenic citrus plants indicated that the transcription level of CcRR5 was associated with root length and lateral root numbers. This was also correlated to the expression of root-related genes and thus confirmed that CcRR5 is involved in the root development. Taken together, the results of this study indicate that CcRR5 is a positive regulator of root growth and CcRR14 directly regulates the expression of CcRR5. Both CcRR5 and CcRR14 can interact with CcSnRK2s.

Engineering zero modes in transformable mechanical metamaterials.

In the field of flexible metamaterial design, harnessing zero modes plays a key part in enabling reconfigurable elastic properties of the metamaterial with unconventional characteristics. However, only quantitative enhancement of certain properties succeeds in most cases rather than qualitative transformation of the metamaterials' states or/and functionalities, due to the lack of systematic designs on the corresponding zero modes. Here, we propose a 3D metamaterial with engineered zero modes, and experimentally demonstrate its transformable static and dynamic properties. All seven types of extremal metamaterials ranging from null-mode (solid state) to hexa-mode (near-gaseous state) are reported to be reversibly transformed from one state to another, which is verified by the 3D-printed Thermoplastic Polyurethanes prototypes. Tunable wave manipulations are further investigated in 1D-, 2D- and 3D-systems. Our work sheds lights on the design of flexible mechanical metamaterials, which can be potentially extended from the mechanical to the electro-magnetite, the thermal or other types.

The introduction to and inspiration from haematological management of major haemorrhage: a British Society for Haematology guideline / 中国输血杂志

Evidenced based and practical guidelines have important role in the decrease of mobility and mortality of the patients with major haemorrhage. Recently, British Society for Haematology updated a guideline on haematological management of major haemorrhage, which provides the recommendations in general and on alternatives to transfusion, obstetric haemorrhage, gastrointestinal haemorrhage, trauma and surgery, and the good practice statements for laboratory/organisational support. The comprehensive and instructive recommendations presented in the guideline will be good references for and assist in the education and development of the guidelines or protocols for the management of the patient with major haemorrhage in China.

Research advances in immunotherapy for hepatocellular carcinoma / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) has an insidious onset, and most patients are in the advanced stage when attending the hospital and thus lose the opportunity for radical surgical resection, which results in the poor prognosis of patients. With the development of clinical treatment, the treatment of advanced HCC has gradually transitioned from the relatively single and limited treatment options in the past to the new model of comprehensive treatment. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has become widely used in clinical practice. At present, a number of clinical studies have been conducted for immunotherapy combined with local and targeted antitumor therapy, and in particular, ICIs combined with targeted therapy have become a research hotspot in the field of HCC treatment. This article reviews the research advances in immunotherapy for the treatment of HCC.

Combined thoracic paravertebral block and interscalene brachial plexus block for modified radical mastectomy: A case report.

BACKGROUND: Modified radical mastectomy (MRM) is the most common surgical treatment for breast cancer. General anesthesia poses a challenge in fragile MRM patients, including cardiovascular instability, insufficient postoperative pain control, nausea and vomiting. Thoracic paravertebral block (TPVB) is adequate for simple mastectomy, but its combination with interscalene brachial plexus block (IBPB) has not yet been proved to be an effective anesthesia method for MRM. CASE SUMMARY: We describe our experience of anesthesia and pain management in 10 patients with multiple comorbidities. An ultrasound-guided TPVB was placed at T2-T3 and T5-T6, and combined with IBPB, with administration of 10, 15 and 5 mL of 0.5% ropivacaine, respectively. A satisfactory anesthetic effect was proved by the absence of ipsilateral tactile sensation within 30 min. Propofol 3 mg/kg/h and oxygen supplementation via a nasal cannula were administered during surgery. None of the patients required additional narcotics, vasopressors, or conversion to general anesthesia. The maximum pain score was 2 on an 11-point numerical rating scale. Two patients required one dose of celecoxib 8 h postoperatively and none reported nausea or emesis. CONCLUSION: This case series demonstrated that combined two-site TPVB and small-volume IBPB with sedation can be used as an alternative anesthetic modality for MRM, providing good postoperative analgesia.

Lignin-Based/Polypyrrole Carbon Nanofiber Electrode With Enhanced Electrochemical Properties by Electrospun Method.

Tailoring the structure and properties of lignin is an important step toward electrochemical applications. In this study, lignin/polypyrrole (PPy) composite electrode films with microporous and mesoporous structures were designed effectively by electrostatic spinning, carbonization, and in situ polymerization methods. The lignin can not only reduce the cost of carbon fiber but also increase the specific surface area of composite films due to the removal of carbonyl and phenolic functional groups of lignin during carbonization. Besides, the compact three-dimensional (3D) conductive network structures were constructed with PPy particles densely coated on the lignin nanofibers, which was helpful to improve the conductivity and fast electron transfer during the charging and discharging processes. The synthesized lignin carbon fibers/PPy anode materials had good electrochemical performance in 1 M H2SO4 electrolyte. The results showed that, at a current density of 1 A g-1, the lignin carbon nanofibers/PPy (LCNFs/PPy) had a larger specific capacitance of 213.7 F g-1 than carbon nanofibers (CNFs), lignin carbon nanofibers (LCNFs), and lignin/PPy fiber (LPAN/PPy). In addition, the specific surface area of LCNFs/PPy reached 872.60 m2 g-1 and the average pore size decreased to 2.50 nm after being coated by PPy. Therefore, the independent non-binder and self-supporting conductive film is expected to be a promising electrode material for supercapacitors with high performance.

Cooling Kinetic Characteristics of Temperature Difference between Cadaver Temperature and Ambient Temperature.

OBJECTIVES: To study the cooling reaction kinetic characteristics of the temperature difference between cadaver temperature and ambient temperature (hereinafter referred to as "cadaver temperature difference") according to the reaction kinetics method. METHODS: Thirty rabbits were randomly divided into 5 groups with 6 rabbits in each group. The rabbits were injected with 10% potassium chloride solution intravenously. After death, the rabbits were placed at 5 ℃, 10 ℃, 15 ℃, 20 ℃ and 25 ℃ environment condition, respectively, and the rectal temperature was measured every minute for 20 hours. The measured cadaver temperature was subtracted from ambient temperature, and the cadaver temperature difference data was calculated using the reaction kinetics formula. The linear regression equation was fitted for analysis, and the experimental results were applied to the temperature difference data of human body after death for verification. RESULTS: Under different environmental conditions, the linear coefficient determination of temperature difference -ln(C/C0) in rabbits was 0.99, showing a good linear relationship with time t. The application of human body temperature data after death was consistent with the results of animal experiments. CONCLUSIONS: Under stable conditions, the temperature difference cooling process after death in rabbits is a first-order kinetic response. The method can also be used to study the temperature difference in human body after death.

Bioinformatics Analysis of Microarray Data in Myelodysplastic Syndrome Based on Gene Expression Omnibus Database / 中国实验血液学杂志

OBJECTIVE@#To identify the key genes and explore mechanisms in the development of myelodysplastic syndrome (MDS) by bioinformatics analysis.@*METHODS@#Two cohorts profile datasets of MDS were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed gene (DEG) was screened by GEO2R, functional annotation of DEG was gained from GO database, gene ontology (GO) enrichment analysis was performed via Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and key genes were screened by Matthews correlation coefficient (MCC) based on STRING database.@*RESULTS@#There were 112 DEGs identified, including 85 up-regulated genes and 27 down-regulated genes. GO enrichment analysis showed that biological processes were mainly enriched in immune response, etc, cellular component in cell membrane, etc, and molecular function in protein binding, etc. KEGG signaling pathway analysis showed that main gene enrichment pathways were primary immunodeficiency, hematopoietic cell lineage, B cell receptor signaling pathway, Hippo signaling pathway, and asthma. Three significant modules were screened by Cytoscape software MCODE plug-in, while 10 key node genes (CD19, CD79A, CD79B, EBF1, VPREB1, IRF4, BLNK, RAG1, POU2AF1, IRF8) in protein-protein interaction (PPI) network were screened based on STRING database.@*CONCLUSION@#These screened key genes and signaling pathways are helpful to better understand molecular mechanism of MDS, and provide theoretical basis for clinical targeted therapy.

Application of remifentanil in postoperative ICU sedation and analgesia in patients with severe craniocerebral trauma / 中国临床药理学与治疗学

AIM: To investigate the effect of remifentanil in the management of sedation and analgesia after severe traumatic brain injury and its influence on the incidence of inflammatory stress. METHODS: From January 2017 to April 2020, 92 patients with severe head trauma surgery in our hospital were selected as the research objects, randomly divided into groups, each with 46 cases. Both groups received postoperative sedation and analgesia management, the control group received dexmedetomidine + 0.9% sodium chloride injection, and the observation group received dexmedetomidine combined with remifentanil. The effects of sedation and analgesia, vital signs, and inflammatory stimuli C reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10)related indicators, serum cortisol, β-endorphin, and the incidence of adverse reactions in the two groups were observed and counted. RESULTS: The scores of sedation and analgesia in the observation group were lower than control group at 2 h, 4 h, and 12 h after administration (P 0.05). CONCLUSION: Remifentanil is used in the management of sedation and analgesia after severe traumatic brain injury, which can effectively improve the effect of sedation and analgesia, reduce inflammatory stimulation, regulate the levels of cortisol, and β-endorphin It is worthy of clinical application.

Transformation of primary myelofibrosis to B-cell acute lymphoblastic leukemia: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the pathogenesis and prognosis of transformation of primary myelofibrosis (PMF) to B-cell acute lymphoblastic leukemia (B-ALL).Methods:The diagnosis and treatment process of a patient transferred from PMF to B-ALL in Affiliated Tumor Hospital of Zhengzhou University in November 2018 were retrospectively analyzed, and the relevant literature was reviewed.Results:The patient was a 64-year-old female, she was initially diagnosed with PMF, and then she developed B-ALL 17 months later after receiving treatment of prednisone, danazole, levamisole, aspirin, thalidomide and jaktinib. After induction therapy, the patient received 8 months of continuous remission, and then the reexamination showed relapse. There was no remission after reinduction therapy. The patient gave up treatment and was discharged 2 months later. JAK2 V617F gene mutation was positive before and after leukemia transformation.Conclusions:The patients with transformation of PMF to B-ALL have poor clinical prognosis and short survival time. The possible mechanism of its transformation may be related to additional genetic events or certain high-risk genes. However, the specific mechanism is still unclear, and further investigation of the etiology is needed to seek targeted treatment.

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway / 世界急诊医学杂志（英文）

@#BACKGROUND: Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis. Our previous study showed that microRNA-761 (miR-761) is overexpressed in hepatocellular carcinoma (HCC) tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis. The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated. METHODS: Exosomal miR-761 was detected in six cell lines. Cell counting kit-8 (CCK-8) and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells. The luciferase reporter assay was used to analyze miR-761 target genes in normal fibroblasts (NFs). The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the transformation of cancer-associated fibroblasts (CAFs). RESULTS: In this study, we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment. We found that HCC-derived exosomal miR-761 was taken up by NFs. Moreover, HCC exosomes affected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2 (SOCS2) and the JAK2/STAT3 signaling pathway. CONCLUSIONS: These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy.

Time-dependent injury of mouse cerebral cortex and hippocampus by acute hypoxia / 生理学报

The aim of this study was to investigate the harmful effects of acute hypoxia on mouse cerebral cortex and hippocampus and the underlying mechanism. Mouse model of acute hypoxia was constructed by using a sealed glass jar. Laser speckle contrast imaging was used to detect the changes of cerebral blood flow after different time duration of hypoxia. Total superoxide dismutase (T-SOD) and malondialdehyde (MDA) assay kits were used to detect oxidative stress in cerebral cortex and hippocampus. Immunofluorescent staining was used to detect neuroinflammatory response of microglia in the cerebral cortex and hippocampus. One-step TUNEL method was used to detect neuronal apoptosis. The results showed that, compared with non-hypoxia (0 min hypoxia) group, 30 min hypoxia group exhibited decreased cerebral blood flow, higher percentage of CD68+/Iba1+ microglia, and increased neural apoptosis in the cerebral cortex and hippocampus. Compared with 30 min group, 60 min hypoxia group showed significantly decreased cerebral blood flow, increased MDA content in the cortex, as well as greater percentage of CD68+/Iba1+ microglia and neuronal apoptosis in the cerebral cortex and hippocampus. These results suggest that acute hypoxia damages brain tissue in a time-dependent manner and the oxidative stress and neuroinflammation are important mechanisms.

Levels and ecological risk of heavy metals in the surface sediments of tidal flats along the North Jiangsu coast, China.

We investigated the contamination levels of nine heavy metals (Mn, Pb, V, Cr, Co, Ni, Cu, Zn, and As) in 153 surface sediment samples collected along five tidal flats on the North Jiangsu coast, China. The spatial distributions of most heavy metals gradually decreased from the northern Sheyang region to the southern Jianggang region, while slightly increasing in the Rudong region. Principal component analysis indicated that Co, Ni, Cu, Zn, and As were mainly derived from the natural environment, V and Cr were mainly derived from human activities. Additionally, Mn and Pb influenced by both natural and human sources. The geo-accumulation index and the contamination factor indicated that heavy metal contamination in the sediments exhibited little to no pollution levels. The potential ecological risk index exhibiting low ecological risks. Meanwhile, the mean probable effect level quotient values indicating slight toxicity. Cr and Ni were the major contributors to toxicity.

Epithelial to Mesenchymal Transition(EMT) Regulated by MicroRNA-429 in Pancreatic Ductal Adenocarcinoma (PDAC).

In this study, we aimed to investigate the role of miRNA-429 in the pathogenesis of pancreatic ductal adenocarcinoma(PDAC) and the potential mechanism of this procedure. Totally 95 consecutive patients with PDAC diagnosed by pathology were retrospectively collected from June 1st , 2015 to August 30th, 2019 in Department of General Surgery, Jingmen First People's Hospital. The human pancreatic cancer cell line Bxpc-3 and Panc-1 were used and the cell proliferation and migration were detected by MTT assays and Transwell assays, respectively. The quantitative real-time polymerase chain reaction (qRT-PCR) was applied to evaluate the expression in RNA level. Our results showed that overexpression of miRNA-429 could suppress the cell invasion, proliferation and metastasis through regulating the process of EMT in PDAC cell line, while low expression of miRNA-429 had the opposite effects. We demonstrated that miRNA-429 had critical roles in the pathogenesis of PDAC. Clinically, we observed that tumor tissues from patients with PDAC exhibited significantly decreasing in miRNA-429 expression compared with the non-tumor tissues. Additionally, decreased expression of miRNA-429 in tumor tissues of patients with PDAC was associated with poorer prognosis and several clinical-pathological characteristics. In conclusion, miRNA-429 exerted anti-tumor functions in PDAC through the regulation of EMT process. The results of this study would provide a novel insight into tumorigenesis and the basis for the development of miRNA-targeting therapies against PDAC.

Clinical analysis of COVID-19 blood recipients: 81 patients / 中国输血杂志

【Objective】 To retrospectively analyze the transfusion records of COVID-19 patients from Feb to Mar 2020 in the Optical Valley Branch of Tongji Hospital in Wuhan, and summarize the clinical features and blood use of those patients. 【Methods】 1) The utilization of blood components in 81 blood recipients were collected and retrospectively analyzed; 2) Propensity score matching (PSM, by the clinical classification of COVID-19) was used to match the transfused and non-transfused patients according to the ratio of 1∶2, and the clinical features of the two groups were compared. 【Results】 The total transfusion rate in our hospital was 5.5%(81/1 463), among which 88.9%(72/81)transfused red blood cell (RBC). Ten patients received RBC transfusion > 20 U, consumed 48.3%(330/680)RBC, 57.5%(53 500/93 100)plasma, 36.2%(42/116)platelets, and 62.3%(114.25/183.25)cryoprecipitates due to ECMO or gastrointestinal bleeding. Compared to non-transfused patients, transfused patients showed worse lab-indexes related to inflammation, infection, and coagulation at admission, higher incidences of acute liver, kidney and cardiac injury, admission to the ICU and mortality(P<0.01). 【Conclusion】 The related functional indexes and prognosis of transfused COVID-19 patients were significantly worse than non-transfused ones. RBC transfusions were dominant, and massive blood transfusions were seldom.

Cryptobiosis-inspired assembly of "AND" logic gate platform for potential tumor-specific drug delivery

Developing tumor-specific drug delivery systems with minimized off-target cargo leakage remains an enduring challenge. In this study, inspired from the natural cryptobiosis explored by certain organisms and stimuli-responsive polyphenol‒metal coordination chemistry, doxorubicin (DOX)-conjugated gelatin nanoparticles with protective shells formed by complex of tannic acid and Fe

Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER

Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents. Here, we defined that norlichexanthone (NOR), a natural product, is a ligand of estrogen receptor-alpha (ER

Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3

The TEA domain (TEAD) family proteins (TEAD1‒4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway. Although the sequences and structures of TEAD family proteins are highly conserved, each TEAD isoform has unique physiological and pathological functions. Therefore, the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases. Here, we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC