Hepatic artery infusion chemotherapy combined with camrelizumab plus rivoceranib for hepatocellular carcinoma with portal vein tumor thrombosis: a multicenter propensity score-matching analysis.

BACKGROUND: Portal vein tumor thrombosis (PVTT) signifies late-stage hepatocellular carcinoma (HCC) with high-risk progression and poor prognosis. As a standard treatment, sorafenib monotherapy has limited the efficacy in managing HCC with PVTT. Currently, both hepatic arterial infusion chemotherapy (HAIC) and the combination of camrelizumab and rivoceranib have shown favorable survival benefits for advanced HCC, surpassing the standard sorafenib treatment. In this study, we investigate the safety and efficacy of HAIC combined with camrelizumab and rivoceranib in treating HCC patients with PVTT. METHODS: From January 2020 to December 2021, HCC patients with PVTT, who received either a triple regime of HAIC combined with camrelizumab and rivoceranib or a dual regime of camrelizumab and rivoceranib as their first-line treatment, were reviewed for eligibility at four hospital centers in China. To balance any intergroup differences, propensity score matching (PSM) was applied. The aim of this study is to compare the efficacy of the dual and triple combination treatment regimens based on survival prognosis and tumor response and evaluate the safety based on the occurrence of adverse reactions. RESULT: In this study, a total of 411 patients who received either the triple treatment regime (HAIC combined with camrelizumab plus rivoceranib, referred to as the HAICCR group, n = 292) or the dual treatment regime (camrelizumab combined with rivoceranib, referred to as the CR group, n = 119) between January 2020 and December 2021 were included. The results showed that the HAICCR group exhibited significantly better overall survival (mOS: 19.60 months vs. 11.50 months, p < 0.0001) and progression-free survival (mPFS: 10.0 months vs. 5.6 months, p < 0.0001) compared to the CR group in the overall cohort. Moreover, the HAICCR group also had a significantly higher ORR (objective response rate, 55.5% vs. 42.0%, p = 0.013) and DCR (disease control rate, 89.0% vs. 79.0%) compared to the CR group. After PSM, a final matched cohort of 83 pairs was obtained, and the survival benefits were consistent in this cohort as well (mOS: 18.70 months vs. 11.0 months, p < 0.0001; mPFS: 10.0 months vs. 5.6 months, p < 0.0001). However, there was no significant difference in the ORR between the triple and dual combination regimes. Univariate and multivariate analysis showed that CTP (Child-Turcotte-Pugh) stage, ALBI (albumin-bilirubin index) grade, tumor number, and treatment regime were significant risk factors affecting overall survival, while AFP (α-fetoprotein) level, tumor number, metastasis, and treatment regime were significant risk factors affecting progression-free survival. As for safety, hypertension and hand-foot syndrome were the two most common adverse reactions in both groups, with no significant difference in the occurrence of adverse reactions between the two groups (p < 0.05). CONCLUSION: In the context of advanced HCC patients with PVTT, the combination regime of HAIC and camrelizumab plus rivoceranib demonstrates more excellent capacity for prolonging survival and offers a well-tolerated safety compared to the CR dual therapy approach. This triple regime represents a therapeutic modality of broad prospects and vast potential for HCC patients with PVTT.

Elucidating the intricacies of the H2S signaling pathway in gasotransmitters: Highlighting the regulation of plant thiocyanate detoxification pathways.

In recent decades, there has been increasing interest in elucidating the role of sulfur-containing compounds in plant metabolism, particularly emphasizing their function as signaling molecules. Among these, thiocyanate (SCN-), a compound imbued with sulfur and nitrogen, has emerged as a significant environmental contaminant frequently detected in irrigation water. This compound is known for its potential to adversely impact plant growth and agricultural yield. Although adopting exogenous SCN- as a nitrogen source in plant cells has been the subject of thorough investigation, the fate of sulfur resulting from the assimilation of exogenous SCN- has not been fully explored. There is burgeoning curiosity in probing the fate of SCN- within plant systems, especially considering the possible generation of the gaseous signaling molecule, hydrogen sulfide (H2S) during the metabolism of SCN-. Notably, the endogenous synthesis of H2S occurs predominantly within chloroplasts, the cytosol, and mitochondria. In contrast, the production of H2S following the assimilation of exogenous SCN- is explicitly confined to chloroplasts and mitochondria. This phenomenon indicates complex interplay and communication among various subcellular organelles, influencing signal transduction and other vital physiological processes. This review, augmented by a small-scale experimental study, endeavors to provide insights into the functional characteristics of H2S signaling in plants subjected to SCN--stress. Furthermore, a comparative analysis of the occurrence and trajectory of endogenous H2S and H2S derived from SCN--assimilation within plant organisms was performed, providing a focused lens for a comprehensive examination of the multifaceted roles of H2S in rice plants. By delving into these dimensions, our objective is to enhance the understanding of the regulatory mechanisms employed by the gasotransmitter H2S in plant adaptations and responses to SCN--stress, yielding invaluable insights into strategies for plant resilience and adaptive capabilities.

Expanding the Hydrophobic Cavity Surface of Azocalix[4]arene to Enable Biotin/Avidin Affinity with Controlled Release.

The development of artificial receptors that combine ultrahigh-affinity binding and controllable release for active guests holds significant importance in biomedical applications. On one hand, a complex with an exceedingly high binding affinity can resist unwanted dissociation induced by dilution effect and complex interferents within physiological environments. On the other hand, stimulus-responsive release of the guest is essential for precisely activating its function. In this context, we expanded hydrophobic cavity surface of a hypoxia-responsive azocalix[4]arene, affording Naph-SAC4A. This modification significantly enhanced its aqueous binding affinity to 1013 M-1, akin to the naturally occurring strongest recognition pair, biotin/(strept-)avidin. Consequently, Naph-SAC4A emerges as the first artificial receptor to simultaneously integrate ultrahigh recognition affinity and actively controllable release. The markedly enhanced affinity not only improved Naph-SAC4A's sensitivity in detecting rocuronium bromide in serum, but also refined the precision of hypoxia-responsive doxorubicin delivery at the cellular level, demonstrating its immense potential for diverse practical applications.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Research progress on the origin, fate, impacts and harm of microplastics and antibiotic resistance genes in wastewater treatment plants.

Previous studies reported microplastics (MPs), antibiotics, and antibiotic resistance genes (ARGs) in wastewater treatment plants (WWTPs). There is still a lack of research progress on the origin, fate, impact and hazards of MPs and ARGs in WWTPs. This paper fills a gap in this regard. In our search, we used "microplastics", "antibiotic resistance genes", and "wastewater treatment plant" as topic terms in Web of Science, checking the returned results for relevance by examining paper titles and abstracts. This study mainly explores the following points: (1) the origins and fate of MPs, antibiotics and ARGs in WWTPs; (2) the mechanisms of action of MPs, antibiotics and ARGs in sludge biochemical pools; (3) the impacts of MPs in WWTPs and the spread of ARGs; (4) and the harm inflicted by MPs and ARGs on the environment and human body. Contaminants in sewage sludge such as MPs, ARGs, and antibiotic-resistant bacteria enter the soil and water. Contaminants can travel through the food chain and thus reach humans, leading to increased illness, hospitalization, and even mortality. This study will enhance our understanding of the mechanisms of action among MPs, antibiotics, ARGs, and the harm they inflict on the human body.

Boron deficiency energizes cyanide uptake and assimilation through activating plasma membrane H+-ATPase in rice plants.

The effect of boron (B) deficiency on mediating the contribution of H+-ATPase in the uptake and assimilation of exogenous cyanide (CN-) is investigated. Under CN- treatments, rice seedlings with B-deficient (-B) conditions exhibited significantly higher CN- uptake and assimilation rates than B-supplemented (+B) seedlings, whereas NH4+ uptake and assimilation rates were slightly higher in -B rice seedlings than in +B. In this connection, the expression pattern of genes encoding ß-CAS, ST, and H+-ATPase was assessed to unravel their role in the current scenario. The abundances of three ß-CAS isogenes (OsCYS-D1, OsCYS-D2, and OsCYS-C1) in rice tissues are upregulated from both "CN--B" and "CN-+B" treatments, however, only OsCYS-C1 in roots from the "CN--B" treatments was significantly upregulated than "CN-+B" treatments. Expression patterns of ST-related genes (OsStr9, OsStr22, and OsStr23) are tissue specific, in which significantly higher upregulation of ST-related genes was observed in shoots from "CN--B" treatments than "CN-+B" treatments. Expression pattern of 7 selected H+-ATPase isogenes, OsA1, OSA2, OsA3, OsA4, OsA7, OsA8, and OsA9 are quite tissue specific between "CN-+B" and "CN--B" treatments. Among these, OsA4 and OsA7 genes were highly activated in the uptake and assimilation of exogenous CN- in -B nutrient solution. These results indicated that B deficiency disturbs the pattern of N cycles in CN--treated rice seedlings, where activation of ST during CN- assimilation decreases the flux of the innate pool of NH4+ produced from CN- assimilation by the ß-CAS pathway in plants. Collectively, the B deficiency increased the uptake and assimilation of exogenous CN- through activating H+-ATPase.

Boron deficiency decreased the root activity of Ga-exposed rice seedlings by reducing iron accumulation and increasing Ga in iron plaque.

Gallium (Ga) is an emerging chemical pollutant chiefly associated with high-tech industries. Boron (B) alleviates the negative effects of toxic elements on plant growth. Thereby, the effects of B fertilization on Ga toxicity in rice seedlings was studied to clarify the role of iron plaque in the distribution of Ga, Fe, and B in Ga-treated rice seedlings in the presence or absence of B. Gallium exposure significantly reduced the biomass of rice seedlings. Boron deficiency induced a significant change in the distribution of B in Ga-treated rice seedlings compared with "Ga+B" treatments. Accumulation of Ga in roots, dithionite-citrate-bicarbonate (DCB) extracts, and shoots showed a dose-dependent manner from both +B and -B rice seedlings. Boron nutrition levels affect the distribution of Fe in roots, DCB extracts, and shoots, in which DCB-extractable Fe was significantly decreased from "Ga-B" treatments compared with "Ga+B" treatments. Root activity was significantly decreased in both Ga-exposed rice seedlings; however, B-deficient seedlings showed a severe reduction than +B rice seedlings. These results reveal that Fe plaque might be a temporary sink for B accumulation when plants are grown with proper B, wherein the re-utilization of DCB-extractable B stored in Fe plaque is mandatory for plant growth under B deficiency. Correlation analysis revealed that B deficiency decreased the root activity of Ga-exposed rice seedlings by reducing DCB-extractable Fe and increasing DCB-extractable Ga in Fe plaque. This study enhances our understanding of how B nutritional levels affect Ga toxicity in rice plants.

Efficiency and safety of hepatic arterial infusion chemotherapy (HAIC) combined with anti-PD1 therapy versus HAIC monotherapy for advanced hepatocellular carcinoma: A multicenter propensity score matching analysis.

PURPOSE: To investigate the clinical efficacy and safety of combination therapy of hepatic arterial infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) therapy in the treatment of advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective clinical research, from March 2018 to December 2019, 1158 HCC patients categorized as BCLC stage C were reviewed for eligibility. We utilized propensity score matching (PSM) to mitigate initial disparities between the groups. The evaluation of the best tumor response was conducted in accordance with mRECIST 1.1 criteria. The difference in survival outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between groups were compared. RESULTS: Following the eligibility review, 453 patients underwent a combined treatment of HAIC with PD1 inhibitors (HAIC-PD1 group), while 221 patients received HAIC monotherapy (HAIC group) met the inclusion criteria and were finally enrolled in this study. In the entire cohort, the HAIC-PD1 group exhibited significantly prolonged overall survival (median overall survival: 40.4 months vs. 9.7 months, p < 0.001) and progression-free survival (median progression-free survival: 22.1 months vs. 5.8 months, p < 0.001). By propensity score, patients were matched according to baseline differences, resulting in all 442 patients in group HAIC-PD1 (n = 221) and group HAIC (n = 221). After PSM adjustment, as well, the survival of the HAIC-PD1 group was still distinctly longer than the HAIC group (median overall survival time, 40.4 months vs 9.7 months, p < 0.001; median progression-free survival, 22.1 months vs 5.7 months, p < 0.001). Univariate and multivariable analysis demonstrated that AFP level, metastasis, and therapeutic schedule were independent predictive factors for overall survival. CONCLUSION: The combination therapy of HAIC and PD1 inhibitors successfully extended OS to advanced HCC patients and could be a better choice than HAIC monotherapy.

Prognosis prediction and risk stratification of transarterial chemoembolization or intraarterial chemotherapy for unresectable hepatocellular carcinoma based on machine learning.

OBJECTIVE: To develop and validate a risk scoring scale model (RSSM) for stratifying prognostic risk after intra-arterial therapies (IATs) for hepatocellular carcinoma (HCC). METHODS: Between February 2014 and October 2022, 2338 patients with HCC who underwent initial IATs were consecutively enrolled. These patients were divided into training datasets (TD, n = 1700), internal validation datasets (ITD, n = 428), and external validation datasets (ETD, n = 200). Five-years death was used to predict outcome. Thirty-four clinical information were input and five supervised machine learning (ML) algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBT), and Random Forest (RF), were compared using the areas under the receiver operating characteristic (AUC) with DeLong test. The variables with top important ML scores were used to build the RSSM by stepwise Cox regression. RESULTS: The CatBoost model achieved the best discrimination when 12 top variables were input, with the AUC of 0.851 (95% confidence intervals (CI), 0.833-0.868) for TD, 0.817 (95%CI, 0.759-0.857) for ITD, and 0.791 (95%CI, 0.748-0.834) for ETD. The RSSM was developed based on the immune checkpoint inhibitors (ICI) (hazard ratios (HR), 0.678; 95%CI 0.549, 0.837), tyrosine kinase inhibitors (TKI) (HR, 0.702; 95%CI 0.605, 0.814), local therapy (HR, 0.104; 95%CI 0.014, 0.747), response to the first IAT (HR, 4.221; 95%CI 2.229, 7.994), tumor size (HR, 1.054; 95%CI 1.038, 1.070), and BCLC grade (HR, 2.375; 95%CI 1.950, 2.894). Kaplan-Meier analysis confirmed the role of RSSM in risk stratification (p < 0.001). CONCLUSIONS: The RSSM can stratify accurately prognostic risk for HCC patients received IAT. On the basis, an online calculator permits easy implementation of this model. CLINICAL RELEVANCE STATEMENT: The risk scoring scale model could be easily implemented for physicians to stratify risk and predict prognosis quickly and accurately, thereby serving as a more favorable tool to strengthen individualized intra-arterial therapies and management in patients with unresectable hepatocellular carcinoma. KEY POINTS: • The Categorical Gradient Boosting (CatBoost) algorithm achieved the optimal and robust predictive ability (AUC, 0.851 (95%CI, 0.833-0.868) in training datasets, 0.817 (95%CI, 0.759-0.857) in internal validation datasets, and 0.791 (95%CI, 0.748-0.834) in external validation datasets) for prediction of 5-years death of hepatocellular carcinoma (HCC) after intra-arterial therapies (IATs) among five machine learning models. • We used the SHapley Additive exPlanations algorithms to explain the CatBoost model so as to resolve the black boxes of machine learning principles. • A simpler restricted variable, risk scoring scale model (RSSM), derived by stepwise Cox regression for risk stratification after intra-arterial therapies for hepatocellular carcinoma, provides the potential forewarning to adopt combination strategies for high-risk patients.

The impact of Sars-Cov-2 infection on the wound healing of cervical treatment in patients with squamous intraepithelial lesions: a retrospective cohort study.

Objective: SARS-CoV-2 infection has been associated with an increase in inflammatory factors, a weakening of the immune system, and a potentially delay in wound healing following surgery or ablative treatment. In this retrospective cohort study, we aimed to investigate the impact of SARS-CoV-2 infection on wound healing following cervical treatment in patients with squamous intraepithelial lesions (SIL). Method: From November 2022 to February 2023, patients with SIL who underwent cervical ablative treatment or loop electrosurgical excision procedure at the People's Hospital of Guangxi Zhuang Autonomous Region, China, were enrolled in the study. Of these, 29 patients who developed symptoms of SARS-CoV-2 infection and confirmed by an antigen test within one month after cervical treatment were included as experimental group, while the other 31 patients who received cervical treatment after recovering from SARS-CoV-2 infection were included in the control group. The cervical wound condition of all patients was documented using colposcopy immediately and one month after the procedure. Image J software was utilized to analyze the wound healing rate at one month post-treatment, and the wound healing status between two groups was compared. A vaginal discharge examination was performed before and one month after cervical treatment. Results: No significant differences in age, severity, treatment, or time between groups. Experimental group had significantly lower healing rate 83.77(62.04, 97.09) % than control 98.64(97.10, 99.46)%，p < 0.001, and a higher scab non-shedding rate (24.14% vs. 3.22%, p = 0.024). Among patients who were infected with SARS-CoV-2 after undergoing cervical treatment, we observed 5 out of 7 patients (71.43%) contracted SARS-CoV-2 within 2 weeks after cervical treatment. No significant correlation was found between white blood cell count or leukocyte esterase in vaginal discharge and delayed wound healing of the cervix (p = 0.947 and 0.970, respectively). Conclusion: SARS-CoV-2 infection may prolong the healing time of cervical treatment in patients with SIL. To minimize the risk of delayed healing, it's crucial for patients to avoid viral infections such as SARS-CoV-2 within the first month of treatment. Taking necessary precautions to prevent infection is essential for successful cervical treatment outcomes in patients with SIL.

Baicalein inhibits apoptosis and autophagy induced by chlorpyrifos exposure to kidney of Cyprinus carpio through activation of PI3K/AKT pathway.

Chlorpyrifos (CPF), a widely used organophosphate pesticide that has caused large-scale contamination globally, has become a major concern. Baicalein (BAI), as a flavonoid extract, shows anti-inflammatory as well as antioxidant activities. The kidneys of fish serve to excrete toxins and are major target organs for environmental contaminants. However, it is not obvious whether BAI can counteract the damage caused by CPF exposure to fish kidneys. Therefore, we conducted a 30-day simulation of CPF poisoning and/or BAI treatment by adding 23.2 µg/L CPF to water and/or 0.15 g/kg BAI to feed. In the transmission electron microscopy results, we observed obvious phenomenon of autophagy and apoptosis in the CPF group, and the TUNEL staining and immunofluorescence of LC3B and p62 double-staining results confirmed that CPF induced autophagy and apoptosis in the kidney of common carp. Furthermore, CPF induced the increase of ROS level and inhibition of PI3K and Nrf2 pathways, which in turn triggered oxidative stress, autophagy and apoptosis in carp kidney according to western blot, RT-qPCR and kit assays. However, addition of BAI significantly alleviated oxidative stress, autophagy and apoptosis due to binding to PI3K protein. Additionally, through phylogenetic tree and structural domain analyses, we also found that the binding sites of BAI and PI3K are conserved in a variety of representative species. These results suggest that BAI antagonizes CPF-caused renal impairments in carp involving the PI3K/AKT pathway and the Nrf2 pathway. Our findings provide new insights into the nephrotoxicity effects of CPF and the potential use of BAI as a detoxification agent for CPF intoxication.

Mathematical Estimation of Endogenous Proline as a Bioindicator to Regulate the Stress of Trivalent Chromium on Rice Plants Grown in Different Nitrogenous Conditions.

The accumulation of proline impacts the defense mechanisms of plants against the harmful effects of adverse environmental conditions; however, its concentration in plants is associated with the metabolism of N. Therefore, the effects of exogenous organic [glutamate (Glu)/arginine (Arg)] and inorganic [nitrate (NO3-)/ammonium (NH4+)] N on the accumulation of proline (Pro) in rice plants under trivalent chromium [Cr(III)] stress were studied through using the mass balance matrix model (MBMM). Application of 'NH4+' showed the largest contribution to the Pro content in rice shoots under different concentrations of Cr(III), followed by 'NO3-', 'Arg', and 'Glu' applications. On the other hand, 'Arg' application displayed the largest contribution to the Pro content in roots under Cr(III) stress, followed by 'NH4+', 'Glu', and 'NO3-' applications. The combined application of 'NH4++Arg' showed the greatest contribution to the Pro content in both roots and shoots of Cr(III)-treated rice seedlings, while the application of 'NO3-+Glu' showed the least contribution to the Pro content in rice seedlings. The current study indicated that the endogenous level of Pro in rice seedlings is quite sensitive to Cr(III) stress under different N sources, and the mathematical modeling showed a reliable result while estimating the relationship between Pro content and N source application.

High power optical frequency comb with 10-19 frequency instability.

Optical frequency combs with more than 10 W have paved the way for extreme ultraviolet combs generation by interaction with inert gases, leading to extreme nonlinear spectroscopy and the ultraviolet nuclear clock. Recently, the demand for an ultra-long-distance time and frequency space transfer via optical dual-comb proposes a new challenge for high power frequency comb in respect of power scaling and optical frequency stability. Here we present a frequency comb based on fiber chirped pulse amplification (CPA), which can offer more than 20 W output power. We further characterize the amplifier branch noise contribution by comparing two methods of locking to an optical reference and measure the out-of-loop frequency instability by heterodyning two identical high-power combs. Thanks to the low noise CPA, reasonable locking method, and optical path-controlled amplifiers, the out-of-loop beat note between two combs demonstrates the unprecedented frequency stability of 4.35 × 10-17 at 1s and 6.54 × 10-19 at 1000 s.

A multitask deep learning radiomics model for predicting the macrotrabecular-massive subtype and prognosis of hepatocellular carcinoma after hepatic arterial infusion chemotherapy.

BACKGROUND: The macrotrabecular-massive (MTM) is a special subtype of hepatocellular carcinoma (HCC), which has commonly a dismal prognosis. This study aimed to develop a multitask deep learning radiomics (MDLR) model for predicting MTM and HCC patients' prognosis after hepatic arterial infusion chemotherapy (HAIC). METHODS: From June 2018 to March 2020, 158 eligible patients with HCC who underwent surgery were retrospectively enrolled in MTM related cohorts, and 752 HCC patients who underwent HAIC were included in HAIC related cohorts during the same period. DLR features were extracted from dual-phase (arterial phase and venous phase) contrast-enhanced computed tomography (CECT) of the entire liver region. Then, an MDLR model was used for the simultaneous prediction of the MTM subtype and patient prognosis after HAIC. The MDLR model for prognostic risk stratification incorporated DLR signatures, clinical variables and MTM subtype. FINDINGS: The predictive performance of the DLR model for the MTM subtype was 0.968 in the training cohort [TC], 0.912 in the internal test cohort [ITC] and 0.773 in the external test cohort [ETC], respectively. Multivariable analysis identified portal vein tumor thrombus (PVTT) (p = 0.012), HAIC response (p < 0.001), HAIC sessions (p < 0.001) and MTM subtype (p < 0.001) as indicators of poor prognosis. After incorporating DLR signatures, the MDLR model yielded the best performance among all models (AUC, 0.855 in the TC, 0.805 in the ITC and 0.792 in the ETC). With these variables, the MDLR model provided two risk strata for overall survival (OS) in the TC: low risk (5-year OS, 44.9%) and high risk (5-year OS, 4.9%). INTERPRETATION: A tool based on MDLR was developed to consider that the MTM is an important prognosis factor for HCC patients. MDLR showed outstanding performance for the prognostic risk stratification of HCC patients who underwent HAIC and may help physicians with therapeutic decision making and surveillance strategy selection in clinical practice.

Experimental and Theoretical Study of the New Leveler Basic Blue 1 during Copper Superconformal Growth.

A novel chlorinated functional group-modified triphenylmethane derivative leveler BB1 is used to achieve superconformal electrodeposition in microvias. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) are performed to study the suppressing effect of BB1, while the convection-dependent adsorption of BB1 on the copper surface is analyzed by galvanostatic measurement, and a BB1 concentration window between 100 and 200 mg/L is beneficial for superfilling. The interactions among BB1, bis-(sodium sulfopropyl) disulfide (SPS), and poly(ethylene glycol) (PEG) are also investigated. Density functional theory (DFT) calculation and in situ Raman spectroscopy are coupled to study the suppression mechanism and synergistic suppression mechanism, namely, the adsorption effect between BB1 and copper substrate, as well as the coordination effect between the modified chlorinated functional group and Cu2+, is proposed. The copper layer becomes smoother and more compact with an increase in BB1 concentration, according to scanning electron microscopy (SEM) and atomic force microscopy (AFM), while X-ray diffraction (XRD) analysis shows that the introduction of BB1 is conducive to the formation of the copper (220) plane. Besides, the solution wettability is boosted by BB1. A copper interconnecting layer with high quality is achieved with 150 mg/L BB1, while the surface deposition thickness (SDT) is about 34 µm and filling percentages (FPs) for microvias with diameters of 100, 125, and 150 µm are 81.34, 82.72, and 81.39%, respectively.

Multiparametric MRI-based model for prediction of local progression of hepatocellular carcinoma after thermal ablation.

PURPOSE: To develop a deep learning radiomics of multiparametric magnetic resonance imaging (DLRMM)-based model that incorporates preoperative and postoperative signatures for prediction of local tumor progression (LTP) after thermal ablation (TA) in hepatocellular carcinoma (HCC). METHODS: From May 2017 to October 2021, 417 eligible patients with HCC were retrospectively enrolled from three hospitals (one primary cohort [PC, n = 189] and two external test cohorts [ETCs][n = 135, 93]). DLRMM features were extracted from T1WI + C, T2WI, and DWI using ResNet18 model. An integrative model incorporating the DLRMM signature with clinicopathologic variables were further built to LTP risk stratification. The performance of these models were compared by areas under receiver operating characteristic curve (AUC) using DeLong test. RESULTS: A total of 1668 subsequences and 31,536 multiparametric MRI slice including T1WI, T2WI, and DWI were collected simultaneously. The DLRMM signatures were extracted from tumor and ablation zone, respectively. Ablative margin, multiple tumors, and tumor abutting major vessels were regarded as risk factors for LTP in clinical model. The AUC of DLRMM model were 0.864 in PC, 0.843 in ETC1, and 0.858 in ETC2, which was higher significantly than those in clinical model (p < 0.001). After integrating clinical variable, DLRMM model obtained significant improvement with AUC of 0.870-0.869 in three cohorts (all, p < 0.001), which can provide the risk stratification for overall survival of HCC patients. CONCLUSIONS: The DLRMM model is essential to identify LTP risk of HCC patients who underwent TA and may potentially benefit personalized decision-making.

A SEER data-based nomogram for the prognostic analysis of survival of patients with Kaposi's sarcoma.

Background: This study developed the first comprehensive nomogram for predicting the cancer-specific survival (CSS) of patients with Kaposi's sarcoma (KS). Methods: Data on the demographic and clinical characteristics of 4143 patients with KS were collected from the Surveillance, Epidemiology, and End Results (SEER) database and used for the prognostic analysis. The patients were randomly divided into two groups: training cohort (n = 2900) and validation cohort (n = 1243). Multivariate Cox regression analysis was used to identify the predictive variables for developing the first nomogram for the survival prediction of patients with KS. The new survival nomogram was further evaluated using the concordance index (C-index), area under the time-dependent receiver operating characteristic curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration plotting, and decision curve analysis (DCA). Results: A nomogram was developed for determining the 3-, 5-, 8-, and 10-year CSS probabilities for patients with KS. The nomogram showed that tumor stage had the greatest influence on the CSS of patients with KS, followed by demographic variables (race, marital status, and age at diagnosis) and other clinical characteristics (surgery status, chemotherapy status, tumor risk classification, and radiotherapy status). The nomogram exhibited excellent performance based on the values of the C-index, AUC, NRI, and IDI as well as calibration plots. DCA further confirmed that the nomogram had good net benefits for 3-, 5-, 8-, and 10-year survival analyses. Conclusions: In this study, by using data from the SEER database, we developed the first comprehensive nomogram for analyzing the survival of patients with KS. This nomogram could serve as a convenient and reliable tool for clinicians to predict CSS probabilities for individual patients with KS.

Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.

Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.

GPS 6.0: an updated server for prediction of kinase-specific phosphorylation sites in proteins.

Protein phosphorylation, catalyzed by protein kinases (PKs), is one of the most important post-translational modifications (PTMs), and involved in regulating almost all of biological processes. Here, we report an updated server, Group-based Prediction System (GPS) 6.0, for prediction of PK-specific phosphorylation sites (p-sites) in eukaryotes. First, we pre-trained a general model using penalized logistic regression (PLR), deep neural network (DNN), and Light Gradient Boosting Machine (LightGMB) on 490 762 non-redundant p-sites in 71 407 proteins. Then, transfer learning was conducted to obtain 577 PK-specific predictors at the group, family and single PK levels, using a well-curated data set of 30 043 known site-specific kinase-substrate relations in 7041 proteins. Together with the evolutionary information, GPS 6.0 could hierarchically predict PK-specific p-sites for 44046 PKs in 185 species. Besides the basic statistics, we also offered the knowledge from 22 public resources to annotate the prediction results, including the experimental evidence, physical interactions, sequence logos, and p-sites in sequences and 3D structures. The GPS 6.0 server is freely available at https://gps.biocuckoo.cn. We believe that GPS 6.0 could be a highly useful service for further analysis of phosphorylation.